Tricyclic urea compounds

ABSTRACT

A compound selected from those of formula (I): in which A, Y, R1, R2 and R3 are as defined in the Specification, and pharmaceutical compositions containing the same, which are useful for treating a mammal afflicted with a disorder of the melatoninergic system.

The present application is a continuation-in-part of our prior-filedcopending application Ser. No. 09/124,197 of Jul. 28, 1998, which inturn was a continuation-in-part of our prior-filed application Ser. No.08/545,395 of Oct. 19, 1995, now U.S. Pat. No. 5,843,986.

The invention relates to new tricyclic carbamide or urea compounds, totheir preparation, and to pharmaceutical compositions which contain themand to the use thereof.

Many studies in the last ten years have demonstrated the fundamentalrole of melatonin (5-methoxy-N-acetyltryptamine) in controlling thecircadian rhythm and endocrine functions, and the melatonin receptorshave been characterized and localized.

In addition to their beneficial effect on disorders of the circadianrhythm (J. Neurosurg., 1985, 63, pp 321-341) and sleep disorders(Psychopharmacology, 1990, 100, pp 222-226), ligands for themelatoninergic system have advantageous pharmacological properties asregards the central nervous system, in particular anxiolytic andantipsychotic lo properties (Neuropharmacology of Pineal Secretions,1990, 8 (3-4), pp 264-272) and analgesic properties (Pharmacopsychiat.,1987, 20, pp 222-223), and for the treatment of Parkinson's disease (J.Neurosurg., 1985, 63, pp 321-341) and Alzheimer's disease (BrainResearch, 1990, 528, pp 170-174). These compounds have likewise shownactivity against certain cancers (Melatonin--Clinical Perspectives,Oxford University Press, 1988, page 164-165), on ovulation (Science1987, 227, pp 714-720) and against diabetes (Clinical Endocrinology,1986, 24, pp 359-364).

Compounds which make it possible to act on the melatoninergic system aretherefore excellent medicaments which can be used by the clinician inthe treatment of the abovementioned pathologies.

The Applicant Company has discovered new tricyclic amide compounds, ofnovel structure, which show a very high affinity for melatoninergicreceptors and which exhibit, in vitro and in vivo, considerablepharmacological and therapeutic advantage.

The invention relates more particularly to the compounds of formula (I):##STR2## in which: R¹ represents a (C₁ -C₄)alkylene chain which isunsubstituted or substituted by a radical chosen from alkyl, hydroxyl,alkoxycarbonyl and carboxyl;

R² represents a hydrogen atom or an alkyl;

R³ represents:

either a group of formula R³¹ ##STR3## in which n represents zero or aninteger from 1 to 3 and R⁵ represents a hydrogen atom, an unsubstitutedor substituted alkyl, an unsubstituted or substituted alkenyl, anunsubstituted or substituted alkynyl, an unsubstituted or substitutedcycloalkyl or an unsubstituted or substituted dicycloalkylalkyl; and X'represents an oxygen or sulfur atom;

or a group of formula R³² : ##STR4## in which X represents an oxygen orsulfur atom, m represents zero or an integer from 1 to 3 and R⁶represents a radical chosen from the same values as R⁵ ;

A represents a chain of formula --O--A¹ -- in which A¹ is a chain chosenfrom (C₂ -C₅)alkylene, (C₂ --C₅)alkenylene and (C₂ -C₅)alkynylene; A¹being unsubstituted or substituted by one or a number of groups chosenfrom alkyl, alkoxy, hydroxyl and oxo,

Y forming, with the benzene ring to which it is bonded, a Y¹ groupchosen from naphthalene, partially hydrogenated naphthalene, benzofuran,partially hydrogenated benzofuran, benzothiophene, partiallyhydrogenated benzothiophene and indole;

it being understood that:

the expression "substituted" relating to the terms "alkyl", "alkenyl"and "alkynyl" means that these groups are substituted by one or a numberof radicals chosen from halogen, alkyl and alkoxy,

the expression "substituted" relating to the term "cycloalkyl" or"dicycloalkylalkyl" means that these groups are substituted by one or anumber of radicals chosen from: alkyl, alkoxy, hydroxyl and the oxogroup,

the terms "alkyl" and "alkoxy" denote radicals containing from 1 to 6carbon atoms,

the terms "alkenyl" and "alkynyl" denote unsaturated radicals containing2 to 6 carbon atoms,

the term "cycloalkyl" denotes a saturated or unsaturated groupcontaining 3 to 8 carbon atoms,

to their enantiomers and diastereoisomers,

and to their addition salts with a pharmaceutically acceptable base.

The invention particularly relates to:

the compounds of formula (I) in which R¹ represents an ethylene chain,

the compounds of formula (I) in which R² represents a hydrogen atom,

the compounds of formula (I) in which R³ represents a group of formulaR³¹,

the compounds of formula (I) in which R⁵ represents an alkyl,

the compounds of formula (I) in which R⁵ represents a cycloalkyl group,

the compounds of formula (I) in which R³ represents an R³² group,

the compounds of formula (I) in which R⁶ represents an alkyl,

the compounds of formula (I) in which R⁶ represents a cycloalkyl,

the compounds of formula (I) in which X' is an oxygen atom,

the compounds of formula (I) in which X' is a sulfur atom,

the compounds of formula (I) in which X is an oxygen atom,

the compounds of formula (I) in which X is a sulfur atom,

the compounds of formula (I) in which A¹ is an ethylene chain,

the compounds of formula (I) in which A¹ is a trimethylene chain,

the compounds of formula (I) in which A¹ is a tetramethylene chain,

the compounds of formula (I) in which A¹ is a vinylene chain,

the compounds of formula (I) in which A¹ is a propenylene chain,

the compounds of formula (I) in which Y forms, with the benzene ring towhich it is bonded, a naphthalene group,

the compounds of formula (I) in which Y forms, with the benzene ring towhich it is bonded, a tetrahydronaphthalene group,

the compounds of formula (I) in which Y forms, with the benzene ring towhich it is bonded, an indole group.

The invention more particularly relates to:

the compounds of formula (I₁) ##STR5## in which A, R¹, R² and R³ are asdefined in the formula (I) and the compounds of formula (I₂) ##STR6## inwhich A, R¹, R² and R³ are as defined in the formula (I).

For example, the invention relates to the compounds of formula (I₃):##STR7## in which A, R² and R³ are as defined in the formula (I) and tothe compounds of formula (I₄) ##STR8## in which A, R² and R³ are asdefined in the formula (I).

Mention may be made, as examples and in a nonlimiting way, among thepharmaceutically acceptable bases which can be used to form an additionsalt with the compounds of the invention, of sodium, potassium, calciumor aluminium hydroxides, alkali metal or alkaline-earth metal carbonatesand organic bases, such as triethylamine, benzylamine, diethanolamine,tert-butylamine, dicyclohexylamine and arginine.

The alkyl radicals present in the formula (I) can be chosen particularlyfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, pentyl or hexyl.

The alkoxy radicals present in the formula (I) can be chosen frommethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,tert-butoxy, pentyloxy and hexyloxy.

The halogens present in the formula (I) can be chosen from bromine,chlorine, fluorine and iodine.

The cycloalkyls present in the formula (I) can be chosen fromcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl.

The alkylene groups present in the formula (I) can be chosen fromethylene, trimethylene, tetramethylene and pentamethylene.

The invention also relates to the process for the preparation of thecompounds of formula (I), wherein a compound of formula (II): ##STR9##in which R¹, R², R³, A¹ and Y have the same definition as in the formula(I) and Z¹ represents a reactive functional group,

is cyclized in order to obtain the corresponding compound of formula(I), ##STR10## in which R¹, R², R³ and Y are as defined above and A isas defined in the formula (I),

which compounds of formula (I) can be, if desired,

purified according to one or a number of purification methods chosenfrom crystallization, silica gel chromatography, extraction, filtrationand passing through charcoal or resin,

separated, if appropriate, in the pure form or in the form of a mixture,into their possible enantiomers or diastereoisomers,

or salified by a pharmaceutically acceptable base.

The invention also relates to a process for the preparation of thecompounds of formula (I), wherein a compound of formula (III): ##STR11##in which A, R¹, R² and Y are as defined in the formula (I), is reacted

a) with an acyl chloride of formula (IV): ##STR12## in which n and R⁵are as defined in the formula (I), or with the corresponding acidanhydride (bis- or mixed-) or with formic acid,

b) or else with an isocyanate of formula (V):

    X═C═N--(CH.sub.2).sub.m --R.sup.6                  (V)

with X, m and R⁶ as defined in the formula (I) in order to obtain,respectively:

a) the compound of formula (I/b1): ##STR13## in which A, Y, R¹, R², R⁵and n are as defined above, or b) the compound of formula (I/b2):##STR14## in which A, Y, R¹, R², R⁶, X and m are as defined above, itbeing possible for the compounds of formula (I/b1) and (I/b2) to be, ifdesired,

purified according to one or a number of purification methods chosenfrom crystallization, silica gel chromatography, extraction, filtrationand passing through charcoal or resin,

separated, if appropriate, in the pure form or in the form of a mixture,into their possible enantiomers or diastereoisomers,

or salified by a pharmaceutically acceptable base.

The compound of formula (I) in which R³¹ represents a --CS--(CH₂)_(n)--R⁵ group can also be obtained from the corresponding compound offormula (I), in which R³¹ represents a --CO--(CH₂)_(n) --R₅ group, whichis subjected to a thionation reagent, for example Lawesson's reagent.

The invention also relates to the preparation of compounds of formula(I/c1): ##STR15## in which R¹, R², R³ and Y are as defined in theformula (I) and A³ represents a (C₂ -C₅)alkylene chain substituted by ahydroxyl radical or a (C₂ -C₅)alkenylene chain, wherein the controlledreduction is carried out of a compound of formula (I/c0): ##STR16## inwhich R¹, R², R³ and Y are as defined above and A² represents a (C₂-C₅)alkylene chain substituted by an oxo group,

it being possible for the compounds of formula (I/c1) to be, if desired,

purified according to one or a number of purification methods chosenfrom crystallization, silica gel chromatography, extraction, filtrationand passing through charcoal or resin,

separated, if appropriate, in the pure form or in the form of a mixture,into their possible enantiomers or diastereoisomers,

or salified by a pharmaceutically acceptable base.

The invention also relates to a process for the preparation of thecompounds of formula (I/d), a specific case of the compounds of formula(I): ##STR17## in which Y, R¹, R² and R³ are as defined in the formula(I) and A⁵ represents a (C₂ -C₅)alkylene chain which is unsubstituted orsubstituted by a (C₁ -C₆)alkyl radical, wherein a compound of formula(VI): ##STR18## in which Y, R¹, R² and R³ are as defined above and A⁶represents a (C₂ -C₅)alkenyl radical which is unsubstituted orsubstituted by a (C₁ -C₆)alkyl radical, is subjected to a cyclizationreaction,

it being possible for the compounds of formula (I/d) to be, if desired,

purified according to one or a number of purification methods chosenfrom crystallization, silica gel chromatography, extraction, filtrationand passing through charcoal or resin,

separated, if appropriate, in the pure form or in the form of a mixture,into their possible enantiomers or diastereoisomers,

or salified by a pharmaceutically acceptable base.

The invention also relates to the compounds of formula (VI): ##STR19##in which R¹, R², R³ and Y are as defined in the formula (I) and A⁶represents a (C₂ -C₅)alkenyl radical which is unsubstituted orsubstituted by a (C₁ -C₆)alkyl radical, which are useful as syntheticintermediates.

The compounds of formula (II) as described above are accessible to aperson skilled in the art by reaction of a compound of formula (II/a):##STR20## in which R¹, R², R³ and Y are as defined in the formula (I),with a compound of formula (II/b):

    Z.sup.2 --A.sup.1 --Z.sup.3                                (II/b)

in which A¹ has the same definition as in the formula (I), Z² representsan optionally protected reactive functional group and Z³ represents aleaving group, for example a halogen atom or a tosyl group.

For example, Z² represents a hydroxyl or carboxyl functional group, adouble bond or a triple bond.

The invention also applies to the compounds of formula (II): ##STR21##in which R¹, R², R³ and A¹ are as defined in the formula (I) and Z¹represents a reactive functional group,

which are useful as synthetic intermediates.

The starting materials used in the processes described above are eithercommercially available or known in the state of the art or are easilyaccessible to a person skilled in the art according to processes whichare well known in the literature. More specific reference will be made,for the compounds of general formula (II), to the descriptions of PatentEP 447,285 and of Patent Application EP 530,087.

The compounds of formula (I) have pharmacological properties which areof great interest the clinician.

The compounds of the invention and the pharmaceutical compositionscontaining them are proving to be useful in the treatment of disordersof the melatoninergic system.

The pharmacological study of the compounds of the invention has in factshown that they were not toxic, that they had a very high selectiveaffinity for melatonin receptors and that they had significantactivities with respect to the central nervous system and, inparticular, therapeutic properties with respect to sleep disorders,anxiolytic, antipsychotic and analgesic properties and properties withrespect to the microcirculation were noted, which make it possible toestablish that the products of the invention are useful in the treatmentof stress, sleep disorders, anxiety, seasonal depressions,cardiovascular pathologies, insomnia and tiredness due to jet lag,schizophrenia, panic attacks, melancholia, eating disorders, obesity,insomnia, psychotic disorders, epilepsy, Parkinson's disease, seniledementia, various disorders related to normal or pathological ageing,migrane, memory losses, Alzheimer's disease and disorders of cerebralcirculation. In another field of activity, it appears that the productsof the invention have ovulation-inhibiting and immunomodulatingproperties and that they are capable of being used in anticancertreatment.

The compounds will preferably be used in the treatment of seasonaldepressions, sleep disorders, cardiovascular pathologies, insomnia andtiredness due to jet lag, eating disorders and obesity.

For example, the compounds will be used in the treatment of seasonaldepressions and sleep disorders.

Another subject of the present invention is the pharmaceuticalcompositions containing the products of formula (I) or, if appropriate,one of their addition salts with a pharmaceutically acceptable base incombination with one or a number of pharmaceutically acceptableexcipients.

Mention can more particularly be made, among the pharmaceuticalcompositions according to the invention, of those which are suitable fororal, parenteral, nasal, per- or transcutaneous, rectal, perlingual,ocular or respiratory administration, may especially be mentioned, andin particular simple or sugar-coated tablets, sublingual tablets,chartulas, packets, gelatin capsules, glossettes, lozenges,suppositories, creams, ointments, dermal gels and imbibable orinjectable phials.

The dosage varies according to the age and weight of the patient, theadministration route, the nature of the therapeutic indication orpossible associated treatments and ranges between 0.1 mg and 1 g per 24hours in 1 or 2 administrations and more particularly 1 to 100 mg, forexample 1 to 10 mg.

The following examples illustrate the invention but do not limit it inany way.

PREPARATION 1 N-{2-[7-(CARBOXYMETHYLOXY)NAPHTH-1-YL]ETHYL}ACETAMIDE##STR22## Reactants: N-[2-(7-Hydroxynaphth-1-yl)ethyl]acetamide: 7 mmol(1.60 g)

Anhydrous acetone: 30 cm³

Potassium carbonate: 14 mmol (1.93 g)

Ethyl bromoacetate: 10 mmol (1.67 g)

Procedure:

The N-[2-(7-hydroxynaphth-1-yl)ethyl]acetamide is dissolved in theanhydrous acetone, the potassium carbonate is added and the mixture isleft stirring at reflux for a half-hour. The ethyl bromoacetate is addeddropwise using a dropping funnel and the mixture is left stirring atreflux for three hours. The mixture is left to cool, the precipitate isfiltered off, the filtrate is evaporated to dryness and the residue isrecrystallized.

Characteristics:

Yield: 80%

Recrystallization solvent: toluene/hexane (1/2)

Melting point: 95-97° C.

Molecular mass: 315.355 g.mol⁻¹ for C₁₂ H₂₁ NO₄

    ______________________________________                                        Microanalysis:                                                                           % C           % H    % N                                           ______________________________________                                        Calculated:                                                                              68.55         6.71   4.49                                          Found:     68.26         6.57   4.71                                          ______________________________________                                        Infrared:                                                                     3300           cm.sup.-1  ν N--H                                           2960-2860      cm.sup.-1  ν C--H alkyls                                    1735           cm.sup.-1  ν C═O ester                                  1620           cm.sup.-1  ν C═O amide                                  ______________________________________                                        NMR (d.sub.6 -DMSO) 300 MHz:                                                  1.25 ppm    triplet     3H  H.sub.f, J.sub.f-e = 7.10 Hz                      1.85 ppm    singlet     3H  H.sub.c                                           3.15 ppm    triplet     2H  H.sub.a, J.sub.a-b = 6.80 Hz                      3.35 ppm    multiplet   2H  H.sub.b                                           4.20 ppm    quartet     2H  H.sub.e                                           5.00 ppm    singlet     2H  H.sub.d                                           7.20-                                                                              ppm    unresolved peak                                                                           3H  H.sub.2, H.sub.3, H.sub.6                         7.35                                                                          7.55 ppm    doublet     1H  H.sub.8, J.sub.8-6 = 2.15 Hz                      7.75 ppm    double doublet                                                                            1H  H.sub.4, J.sub.4-3 = 7.40 Hz, J.sub.4-2 =                                     2.60 Hz                                           7.85 ppm    doublet     1H  H.sub.5, J.sub.5-6 = 9.00 Hz                      8.05 ppm    triplet     1H  N--H amide                                        ______________________________________                                         ##STR23##     Reactants: N-{2-[7-(Ethoxycarbonylmethyloxy)naphth-1-yl]ethyl}acetamide: 5     mmol (1.57 g)

10% Aqueous sodium hydroxide solution: 10 mmol (40 cm³)

Procedure:

The N-[2-[7-(ethoxycarbonylmethyloxy)naphth-1-yl]ethyl]acetamide and a10% aqueous sodium hydroxide solution are introduced into a flask andleft to stir at room temperature until dissolution is complete. Thereaction mixture is cooled in an ice bath and acidified with aconcentrated hydrochloric acid solution. The precipitate is filteredoff, washed with water, dried and recrystallized.

Characteristics:

Yield: 70%

Recrystallization solvent: alcohol/water (2/1)

Melting point: 181-184° C.

Molecular mass: 296.311 g.mol⁻¹ for C₁₆ H₁₇ NO₄ +0.5H₂ O

    ______________________________________                                        Microanalysis:                                                                           % C           % H    % N                                           ______________________________________                                        Calculated:                                                                              64.85         6.12   4.72                                          Found:     64.84         5.77   4.87                                          ______________________________________                                        Infrared:                                                                     3320           cm.sup.-1  ν N--H amide                                     2920-2860      cm.sup.-1  ν C--H alkyls                                    2500           cm.sup.-1  ν CO.sub.2 H                                     1700           cm.sup.-1  ν C═O acide                                  1610           cm.sup.-1  ν C═O amide                                  ______________________________________                                        NMR (d.sub.6 -DMSO) 300 MHz:                                                  1.80 ppm    singlet     3H  H.sub.c                                           3.10 ppm    triplet     2H  H.sub.a, J.sub.a-b = 7.15 Hz                      3.35 ppm    quartet     2H  H.sub.b                                           4.90 ppm    singlet     2H  H.sub.d                                           7.30 ppm    unresolved peak                                                                           3H  H.sub.2, H.sub.3, H.sub.6                         7.55 ppm    singlet     1H  H.sub.8                                           7.80 ppm    doublet     1H  H.sub.4, J.sub.4-3 = 7.15 Hz                      7.90 ppm    doublet     1H  H.sub.5, J.sub.5-6 = 8.60 Hz                      8.10 ppm    signal      1H  N--H                                              13.00                                                                              ppm    signal      1H  O--H, acidic, disappears with D.sub.2             ______________________________________                                                                    O                                             

PREPARATION 2 N-{2-[7-(PROPARGYLOXY)NAPHTH-1-YL]ETHYL}ACETAMIDE##STR24## Reactants: N-[2-(7-hydroxynaphth-1-yl)ethyl]acetamide: 5 mmol(1.15 g)

Sodium hydride: 18.75 mmol (0.45 g)

Tosylate of propargyl alcohol: 20 mmol

Dimethylformamide: 30 cm³

Procedure:

The N-[2-(7-hydroxynaphth-1-yl)ethyl]acetamide and the dimethylformamideare introduced into a three-necked, round-bottomed flask, the sodiumhydride is added in small portions and the reaction mixture is leftstirring for two hours under nitrogen at room temperature. The tosylateof propargyl alcohol is added dropwise using a dropping funnel and thereaction mixture is left stirring for a half-hour under nitrogen. Thereaction mixture is poured into water with stirring and extracted withethyl acetate, the extract is washed with water, dried over calciumchloride, filtered and evaporated to dryness and the residue isrecrystallized.

Characteristics:

Yield: 59%

Recrystallization solvent: hexane/toluene (2/1)

Melting point: 87-89° C.

Molecular mass: 267.313 g.mol⁻¹ for C₁₇ H₁₇ NO₂

    ______________________________________                                        Microanalysis:                                                                           % C           % H    % N                                           ______________________________________                                        Calculated:                                                                              76.37         6.41   5.24                                          Found:     76.12         6.30   5.33                                          ______________________________________                                        Infrared:                                                                     3270          cm.sup.-1  ν N--H                                            3200          cm.sup.-1  ν C.tbd.C--H                                      2100          cm.sup.-1  ν C.tbd.C                                         1620          cm.sup.-1  ν C═O amide                                   ______________________________________                                        NMR (d.sub.6 -DMSO) 300 MHz:                                                  1.85    ppm     singlet      3H   H.sub.c                                     3.15    ppm     triplet      2H   H.sub.a, J.sub.a-b = 6.70 Hz                3.30    ppm     multiplet    2H   H.sub.b                                     3.60    ppm     singlet      1H   H.sub.e                                     5.00    ppm     singlet      2H   H.sub.d                                     7.20-7.35                                                                             ppm     unresolved peak                                                                            3H   H.sub.2, H.sub.3, H.sub.6                   7.65    ppm     singlet      1H   H.sub.8                                     7.75    ppm     doublet      1H   H.sub.4, J.sub.4-3 = 7.40 Hz                7.85    ppm     doublet      1H   H.sub.5, J.sub.-6 = 9.00 Hz                 8.05    ppm     signal       1H   NH amide                                    ______________________________________                                    

By proceeding in an analogous way, the following preparations areobtained:

PREPARATION 3 N-{2-[7-(CARBOXYMETHYLOXY)NAPHTH-1-YL]ETHYL}-PROPIONAMIDEPREPARATION 4 N-{2-[7-(CARBOXYMETHYLOXY)NAPHTH-1-YL]ETHYL}-BUTYRAMIDEPREPARATION 5 N-{2-[7-(CARBOXYMETHYLOXY)NAPHTH-1-YL]ETHYL}-ISOBUTYRAMIDEPREPARATION 6N-{2-[7-(CARBOXYMETHYLOXY)NAPHTH-1-YL]ETHYL}-TRIFLUOROACETAMIDEPREPARATION 7 N-{2-[7-(CARBOXYMETHYLOXY)NAPHTH-1-YL]ETHYL}FORMAMIDEPREPARATION 8 N-{2-[7-(CARBOXYMETHYLOXY)NAPHTH-1-YL]ETHYL}PENTANAMIDEPREPARATION 9 N-{2-[7-(CARBOXYMETHYLOXY)NAPHTH-1-YL]ETHYL}IODOACETAMIDEPREPARATION 10N-{2-[7-(CARBOXYMETHYLOXY)NAPHTH-1-YL]ETHYL}-CYCLOPROPANECARBOXAMIDEPREPARATION 11N-{2-[7-(CARBOXYMETHYLOXY)NAPHTH-1-YL]ETHYL}-CYCLOBUTANECARBOXAMIDEPREPARATION 12N-{2-[7-(CARBOXYMETHYLOXY)NAPHTH-1-YL]ETHYL}-CYCLOPENTANECARBOXAMIDEPREPARATION 13N-{2-[7-(CARBOXYMETHYLOXY)NAPHTH-1-YL]ETHYL}-CYCLOHEXANECARBOXAMIDEPREPARATION 14N-{2-[7-(CARBOXYMETHYLOXY)NAPHTH-1-YL]ETHYL}-PROPENE-1-CARBOXAMIDEPREPARATION 15N-{2-[7-(CARBOXYMETHYLOXY)NAPHTH-1-YL]ETHYL}-N'-METHYLUREA PREPARATION16 N-{2-[7-(CARBOXYMETHYLOXY)NAPHTH-1-YL]ETHYL}-N'-ETHYLUREA PREPARATION17 N-{2-[7-(CARBOXYMETHYLOXY)NAPHTH-1-YL]ETHYL}-N'-n-PROPYLUREAPREPARATION 18N-{2-[7-(CARBOXYMETHYLOXY)NAPHTH-1-YL]ETHYL}-N'-CYCLOPROPYLUREAPREPARATION 19N-{2-[7-(CARBOXYMETHYLOXY)NAPHTH-1-YL]ETHYL}N'-n-PROPYLTHIOUREAPREPARATION 20N-{2-[7-(CARBOXYMETHYLOXY)NAPHTH-1-YL]ETHYL}-N'-CYCLOPROPYLTHIOUREAPREPARATION 21 N-{2-[7-(PROPARGYLOXY)NAPHTH-1-YL]ETHYL}-PROPIONAMIDEPREPARATION 22 N-{2-[7-(PROPARGYLOXY)NAPHTH-1-YL]ETHYL}-BUTYRAMIDEPREPARATION 23 N-{2-[7-(PROPARGYLOXY)NAPHTH-1-YL]ETHYL}-ISOBUTYRAMIDEPREPARATION 24N-{2-[7-(PROPARGYLOXY)NAPHTH-1-YL]ETHYL}TRIFLUOROACETAMIDE PREPARATION25 N-{2-[7-(PROPARGYLOXY)NAPHTH-1-YL]ETHYL}FORMAMIDE PREPARATION 26N-{2-[7-(PROPARGYLOXY)NAPHTH-1-YL]ETHYL}-PENTANAMIDE PREPARATION 27N-{2-[7-(PROPARGYLOXY)NAPHTH-1-YL]ETHYL}-IODOACETAMIDE PREPARATION 28N-{2-[7-(PROPARGYLOXY)NAPHTH-1-YL]ETHYL}CYCLOPROPANECARBOXAMIDEPREPARATION 29N-{2-[7-(PROPARGYLOXY)NAPHTH-1-YL]ETHYL}CYCLOBUTANECARBOXAMIDEPREPARATION 30N-{2-[7-(PROPARGYLOXY)NAPHTH-1-YL]ETHYL}CYCLOPENTANECARBOXAMIDEPREPARATION 31N-{2-[7-(PROPARGYLOXY)NAPHTH-1-YL]ETHYL}CYCLOHEXANECARBOXAMIDEPREPARATION 32N-{2-[7-(PROPARGYLOXY)NAPHTH-1-YL]ETHYL}PROPENE-1-CARBOXAMIDEPREPARATION 33 N-{2-[7-(PROPARGYLOXY)NAPHTH-1-YL]ETHYL}-N'-METHYLUREAPREPARATION 34 N-{2-[7-(PROPARGYLOXY)NAPHTH-1-YL]ETHYL}N'-ETHYLUREAPREPARATION 35 N-{2-[7-(PROPARGYLOXY)NAPHTH-1-YL]ETHYL}-N'-PROPYLUREAPREPARATION 36N-{2-[7-(PROPARGYLOXY)NAPHTH-1-YL]ETHYL}-N'-CYCLOPROPYLUREA PREPARATION37 N-{2-[7-(PROPARGYLOXY)NAPHTH-1-YL]ETHYL}-N'-METHYLTHIOUREAPREPARATION 38N-{2-[7-(PROPARGYLOXY)NAPHTH-1-YL]ETHYL}-N'-CYCLOPROPYLTHIOUREAPREPARATION 39 2-[7H-8,9-DIHYDROPYRANO[3,2-e]INDOLYL]ETHYLAMINE

This compound is described in J. Med. Chem., 1992, 35, p. 3625-3632.

PREPARATION 40 N-[2-(8-ALLYL-7-HYDROXYNAPHTH-1-YL)ETHYL]ACETAMIDE##STR25## Reactants: 2-(7-Methoxynaphth-1-yl)ethylamine hydrochloride:58 mmol (13.8 g)

47% Aqueous HBr solution: 390 mmol (46 cm³)

Procedure:

The ethylamine hydrochloride and the 47% HBr solution are introducedinto a 250 cm³ round-bottomed flask. The mixture is brought to refluxfor 5 hours. After cooling, the reaction mixture is filtered.

Characteristics:

Molecular mass: 268.16 g for C₁₂ H₁₄ BrNO

Appearance: white solid

Melting point: 174-175° C.

R_(f) : 0.72 eluent: methanol/28% aqueous ammonia (4/1)

Yield: 80%

Recrystallization solvent: ethyl acetate/hexane (1/3)

    ______________________________________                                        Infrared:                                                                     3240-3460      cm.sup.-1 ν OH                                              3040-3100      cm.sup.-1 ν C═C twisting                                2950-3060      cm.sup.-1 ν CH                                              2720-2480      cm.sup.-1 ν NH.sub.3.sup.+                                  ______________________________________                                        NMR (d.sub.6 -DMSO, δ) 80 MHz:                                          3.0-3.4                                                                              ppm     unresolved peak                                                                            4H   H.sub.2, H.sub.3                             7.0-7.9                                                                              ppm     unresolved peak                                                                            6H   H, aromatic protons                          8.1    ppm     singlet      3H   H.sub.4                                      9.8    ppm     singlet      1H   H.sub.1                                      ______________________________________                                        Microanalysis:                                                                           % C           % H    % N                                           ______________________________________                                        Calculated:                                                                              53.75         5.26   5.22                                          Found:     53.84         5.30   5.32                                          ______________________________________                                         ##STR26##     Reactants: 2-(7-Hydroxynaphth-1-yl)ethylamine hydrobromide: 3.8 mmol (1.02     g)

Sodium carbonate: 8.5 mmol (0.90 g)

Acetyl chloride: 3.8 mmol (0.30 g)

Procedure:

The sodium carbonate is dissolved in 5 cm³ of water in a 50 cm³ flaskand the hydrobromide is added with stirring. 20 cm³ of ethyl acetate areadded to the suspension obtained and then the acetyl chloride is run indropwise. Stirring is maintained for 30 minutes (the solution is clear).The organic phase is extracted with water, then with a 1N aqueous HClsolution and then with water until the wash liquors are neutral. Theorganic phase is dried over magnesium sulfate, filtered and dried underreduced pressure.

Characteristics:

Molecular mass: 229.27 g for C₁₄ H₁₅ BrNO₂

Appearance: white solid

Melting point: 125-126° C.

R_(f) : 0.32 eluent: acetone/toluene/cyclohexane (4/4/2)

Yield: 60%

Recrystallization solvent: water

    ______________________________________                                        Infrared:                                                                     3340          cm.sup.-1   ν OH                                             2980          cm.sup.-1   ν CH                                             1460          cm.sup.-1   ν CH.sub.3                                       1640          cm.sup.-1   ν CO amide                                       ______________________________________                                        NMR (CDCl.sub.3, δ) 80 MHz:                                             2.0   ppm    singlet     3H  H.sub.5                                          3.2   ppm    triplet     2H  H.sub.2, J.sub.2-3 =7.1 Hz                       3.6   ppm    quintet     2H  H.sub.3, J.sub.3-2 = 7.1 Hz, J.sub.3-4 = 7.1                                  Hz                                               5.8   ppm    signal      1H  H4                                               7.0-7.9                                                                             ppm    unresolved peak                                                                           6H  H, aromatic protons                              9.5   ppm    singlet     1H  H1                                               ______________________________________                                        Microanalysis:                                                                           % C           % H    % N                                           ______________________________________                                        Calculated:                                                                              73.34         6.59   6.11                                          Found:     72.99         6.57   6.29                                          ______________________________________                                         ##STR27##     Reactants: N-[2-(7-Hydroxynaphth-1-yl)ethyl]acetamide: 20 mmol (5 g)

Sodium carbonate: 50 mmol (6.63 g)

Allyl bromide: 30 mmol (3.63 g)

Procedure:

The compound obtained in the preceding stage is dissolved in 100 cm³ ofanhydrous acetone. The sodium carbonate is added and the reactionmixture is left stirring at reflux for 30 minutes. The allyl bromide isadded dropwise. The reaction mixture is left at reflux and with stirringfor 3 hours. After cooling, the reaction mixture is filtered and thefiltrate is dried under reduced pressure. The oil obtained is purifiedby column chromatography.

Characteristics:

Molecular mass: 269.33 g for C₁₇ H₁₉ NO₂

Appearance: oil

R_(f) : 0.19 eluent: acetone/toluene/cyclohexane (2/3/5)

Yield: 87%

    ______________________________________                                        Infrared:                                                                     3260            cm.sup.-1  ν NH amide                                      2920-2840       cm.sup.-1  ν CH                                            1635            cm.sup.-1  ν CO amide                                      1590            cm.sup.-1  ν C═C                                       ______________________________________                                        NMR (CDCl.sub.3, δ) 300 MHz:                                            1.90  ppm     singlet     3H  H.sub.g                                         3.20  ppm     triplet     2H  H.sub.e J.sub.e-d = 7.00 Hz                     3.60  ppm     quintet     2H  H.sub.d                                         4.70  ppm     doublet     2H  H.sub.c J.sub.c-b = 5.28 Hz                     5.30  ppm     doublet     1H  H.sub.a cis,                                                                          J.sub.a-b = 10.46 Hz                    5.50  ppm     doublet     1H  H.sub.a trans,                                                                        J.sub.a-b = 17.30 Hz                    5.60  ppm     signal      1H  H.sub.f                                         6.15  ppm     multiplet   1H  H.sub.b                                         7.15  ppm     double doublet                                                                            1H  H.sub.6 J.sub.ortho = 8.90                                                            J.sub.meta = 2.30                       7.25  ppm     multiplet   2H  H.sub.2,3                                       7.40  ppm     doublet     1H  H.sub.8                                         7.65  ppm     multiplet   1H  H.sub.3                                         7.75  ppm     doublet     1H  H.sub.5 J.sub.ortho = 8.30                      ______________________________________                                        Microanalysis:                                                                           % C           % H    % N                                           ______________________________________                                        Calculated:                                                                              75.80         7.11   5.20                                          Found:     75.75         7.15   5.20                                          ______________________________________                                         ##STR28##     Reactants: N-[2-(7-Allyloxynaphth-1-yl)ethyl]acetamide: 7.4 mmol (2 g)

N,N-Dimethylaniline: 7.4 mmol (10 cm³)

Procedure:

The N-[2-(7-allyloxynaphth-1-yl)ethyl]acetamide is dissolved in theN,N-dimethylaniline and the reaction mixture is brought to reflux (200°C.) for 2 hours. After cooling, 20 cm³ of ether are added and theorganic phase is extracted with a 10% aqueous sodium hydroxide solutionand then with water. The aqueous phase is then acidified with a 6Naqueous HCl solution and left stirring for a few minutes. Theprecipitate obtained is filtered.

Characteristics:

Molecular mass: 269.33 g.mol⁻¹ for C₁₇ H₁₉ NO₂

Appearance: pale yellow solid

R_(f) : 0.38 eluent: acetone/toluene/cyclohexane (4/4/2)

Melting point: 157-159° C.

Yield: 84%

Recrystallization solvent: cyclohexane

    ______________________________________                                        Infrared:                                                                     3280            cm.sup.-1  ν NH amide                                      2860-3000       cm.sup.-1  ν CH                                            1600            cm.sup.-1  ν CO amide                                      ______________________________________                                        NMR (d.sub.6 -DMSO, δ) 300 MHz:                                         1.83  ppm     singlet   3H   H.sub.h                                          3.20  ppm     signal    2H   H.sub.e                                          3.25  ppm     signal    2H   H.sub.f                                          3.90  ppm     signal    2H   H.sub.d                                          4.65  ppm     doublet   1H   H.sub.b trans, J.sub.b-c = 17.2 Hz               4.95  ppm     doublet   1H   H.sub.b cis, J.sub.b-c = 8.8 Hz                  6.05  ppm     multiplet 1H   H.sub.c                                          7.17  ppm     signal    1H   H.sub.6                                          7.18  ppm     signal    1H   H.sub.3, J.sub.3-2 = 7.4 Hz, J.sub.3-4 =                                      4.33 Hz                                          7.21  ppm     signal    1H   H.sub.2, J.sub.2-3 = 7.5 Hz                      7.65  ppm     signal    1H   H.sub.4, J.sub.4-3 = 7.4 Hz                      7.67  ppm     signal    1H   H.sub.5, J.sub.5-6 = 8.6 Hz                      8.08  ppm     signal    1H   H.sub.g                                          9.60  ppm     singlet   1H   H.sub.a, exchangeable in D.sub.2 O               ______________________________________                                    

PREPARATION 41 N-[2-(8-ALLYL-7-HYDROXYNAPHTH-1-YL)ETHYL]-N'-METHYLUREAEXAMPLE 1 2,3-DIHYDRO-3-OXO-4-(2-ACETAMIDOETHYL)-1-NAPHTHO[2,1-b]-FURAN##STR29## Reactants:N-(2-[7-(Carboxymethyloxy)naphth-1-yl]ethyl)acetamide (Preparation 1):10 mmol (2.9 g)

Polyphosphoric acid: 30 g

Procedure:

The N-{2-[7-(carboxymethyloxy)naphth-1-yl]ethyl}acetamide and thepolyphosphoric acid are introduced into a 100 cm³ round-bottomed flaskwith a ground-glass neck and the reaction mixture is stirred using amechanical stirrer at 85° C. for two hours and a half. The reactionmixture is left stirring for one hour and is poured into ice-old water.Extraction is carried out with ethyl acetate and the organic phase iswashed twice with a 10% aqueous sodium carbonate solution, then washedwith water, dried over calcium chloride, filtered and evaporated todryness. The product is purified on a column with 60 Å silica gel, usingthe acetone/toluene (1/1) eluent.

Characteristics:

Yield: 32%

Recrystallization solvent: hexane/toluene (2/1)

Melting point: 157-158° C.

Molecular mass: 269.287 g.mol⁻¹ for C₁₆ H₁₅ NO₃

    ______________________________________                                        Microanalysis:                                                                           % C           % H    % N                                           ______________________________________                                        Calculated:                                                                              71.35         5.61   5.20                                          Found:     71.33         5.46   5.17                                          ______________________________________                                        Infrared:                                                                     3270           cm.sup.-1  ν N--H amide                                     2920-2860      cm.sup.-1  ν C--H alkyl                                     1685           cm.sup.-1  ν C═O ketone                                 1610           cm.sup.-1  ν C═O amide                                  ______________________________________                                        NMR (d.sub.6 -DMSO) 300 MHz:                                                  1.75    ppm     singlet      3H    H.sub.c                                    3.25    ppm     quartet      2H    H.sub.b                                    3.60    ppm     triplet      2H    H.sub.a, J.sub.a-b = 6.60 Hz               7.45    ppm     unresolved peak                                                                            3H    H.sub.5, H.sub.6, H.sub.9                  7.75    ppm     signal       1H    N--H                                       7.85    ppm     doublet      1H    H.sub.7, J.sub.7-6 = 7.40 Hz               8.30    ppm     doublet      1H    H.sub.8, J.sub.8-9 = 9.00                  ______________________________________                                                                           Hz                                     

EXAMPLE 22,3-DIHYDRO-3-HYDROXY-(2-ACETAMIDOETHYL)-1-NAPHTHO-[2,1-b]FURAN##STR30## Reactants:2,3-Dihydro-3-oxo-4-(2-acetamidoethyl)-1-naphtho[2,1-b]furan (Example1): 5 mmol (1.35 g)

Methanol: 30 cm³

Sodium borohydride: 10 mmol (0.32 g)

Procedure:

The 2,3-dihydro-3-oxo-4-(2-acetamidoethyl)-1-naphtho[2,1-b]furan and themethanol are introduced into a 100 cm³ flask with a ground-glass neck,the sodium borohydride (5 mmol) is added in small portions and thereaction mixture is left stirring. After two hours, sodium borohydride(5 mmol) is added in small portions and the reaction mixture is left tostir overnight at room temperature. The reaction mixture is evaporatedto dryness and the residue is taken up in water and acidified with a 6Nhydrochloric acid solution. The precipitate is filtered off, washed withwater until the wash liquors are neutral, dried and recrystallized fromtoluene.

Characteristics:

Yield: 51%

Melting point: 153-156° C.

Molecular mass: 271.303 g.mol⁻¹ for C₁₆ H₁₇ NO₃

    ______________________________________                                        Microanalysis:                                                                           % C           % H    % N                                           ______________________________________                                        Calculated:                                                                              70.82         6.31   5.16                                          Found:     70.61         6.28   5.04                                          ______________________________________                                        Infrared:                                                                     3250         cm.sup.-1  ν O--H and N--H                                    1620         cm.sup.-1  ν C═O amide                                    ______________________________________                                        NMR (d.sub.6 -DMSO) 300 MHz:                                                  1.80 ppm    singlet     3H  H.sub.c                                           3.00-                                                                              ppm    unresolved peak                                                                           4H  H.sub.a, H.sub.b                                  3.65                                                                          4.50 ppm    multiplet   2H  H.sub.2                                           5.60 ppm    doublet     1H  OH, disappears with D.sub.2 O, J = 7.00           5.70 ppm    multiplet   1H  H.sub.3                                           7.20-                                                                              ppm    unresolved peak                                                                           3H  H.sub.5, H.sub.6, H.sub.9                         7.35                                                                          7.75 ppm    doublet     1H  H.sub.7, J.sub.7-6 = 7.85 Hz                      7.90 ppm    doublet     1H  H.sub.8, J.sub.8-9 = 8.80 Hz                      8.05 ppm    signal      1H  N--H amide                                        ______________________________________                                    

EXAMPLE 3 4-(2-ACETAMIDOETHYL)-1-NAPHTHO[2,1-b]FURAN ##STR31##Reactants: 2,3-Dihydro-3-oxo-4-(2-acetamidoethyl)-1-naphtho[2, 1-b]furan(Example 1): 5 mmol (1.38 g)

Methanol: 30 cm³

Sodium borohydride: 20 mmol (0.76 g)

Procedure:

The 2,3-dihydro-3-oxo-4-(2-acetamidoethyl)-1-naphtho[2,1-b]furan and themethanol are introduced into a 100 cm³ round-bottomed flask and 10 mmolof sodium borohydride are added in small portions with stirring.

After two hours, sodium borohydride (10 mmol) is added in small portionswith stirring. The reaction mixture is left stirring at room temperatureand acidified with a 6N hydrochloric acid solution, the methanol isevaporated, the residue is taken up in water and the precipitate isfiltered off, washed with water until the wash liquors are neutral,dried and recrystallized from toluene/hexane.

Yield: 85%

Melting point: 142-144° C.

Molecular mass: 253.287 g.mol⁻¹ for C₁₆ H₁₅ NO₂

    ______________________________________                                        Microanalysis:                                                                           % C           % H    % N                                           ______________________________________                                        Calculated:                                                                              75.80         5.96   5.53                                          Found:     75.57         5.97   5.47                                          ______________________________________                                        Infrared:                                                                     3240          cm.sup.-1  ν N--H amide                                      1625          cm.sup.-1  ν C═O amide                                   ______________________________________                                        NMR (d.sub.6 -DMSO) 300 MHz:                                                  1.85      ppm     singlet      3H   H.sub.c                                   3.40      ppm     multiplet    4H   H.sub.a, H.sub.b                          7.50      ppm     multiplet    2H   H.sub.3, H.sub.9                          7.80-7.95 ppm     unresolved peak                                                                            4H   H.sub.5, H.sub.6, H.sub.7, H.sub.8        8.20      ppm     multiplet    2H   H.sub.2, NH                               ______________________________________                                    

EXAMPLE 4 5-(2-ACETAMIDOETHYL)-2H-1-NAPHTHO[2,1-b]PYRAN ##STR32##Reactants: N-{2-[7-(Propargyloxy)naphth-1-yl]ethyl}acetamide(Preparation 2): 10 mmol (2.67 g)

Triethylene glycol: 40 cm³

Procedure:

The N-{2-[7-(propargyloxy)naphth-1-yl]ethyl}acetamide and thetriethylene glycol are introduced into a two-necked, round-bottomedflask. The reaction mixture is heated at 160°-170° C. under nitrogen andwith stirring for five hours. The reaction mixture is poured intoice-cold water and extracted with ethyl acetate and the extract iswashed with water, dried over calcium chloride, filtered and evaporatedto dryness.

The product is purified on a 60 Å silica column with an acetone/toluene(1/1) eluent.

Characteristics:

Yield: 23%

Recrystallization solvent: toluene/hexane

Melting point: decomposes at 113° C.

Molecular mass: 267.313 g.mol⁻¹ for C₁₇ H₁₇ NO₂

    ______________________________________                                        Microanalysis:                                                                           % C           % H    % N                                           ______________________________________                                        Calculated:                                                                              76.37         6.41   5.24                                          Found:     76.16         6.40   5.52                                          ______________________________________                                        Infrared:                                                                     3250           cm.sup.-1  ν N--H                                           2960-2840      cm.sup.-1  ν C--H alkyls                                    1630           cm.sup.-1  ν C═O amide                                  ______________________________________                                        NMR (d.sub.6 -DMSO) 300 MHz:                                                  1.80    ppm     singlet      3H   H.sub.c                                     3.20    ppm     triplet      2H   H.sub.a, J.sub.a-b = 6.80 Hz                3.40    ppm     multiplet    2H   H.sub.b                                     4.65    ppm     doublet      2H   H.sub.2, J.sub.2-3 = 4.30 Hz                5.90    ppm     multiplet    1H   H.sub.3                                     7.10    ppm     doublet      1H   H.sub.4, J.sub.4-3 = 8.80 Hz                7.30    ppm     unresolved peak                                                                            3H   H.sub.6, H.sub.7, H.sub.10                  7.70    ppm     doublet      1H   H.sub.8, J.sub.8-7 = 7.50 Hz                7.80    ppm     doublet      1H   H.sub.9, J.sub.9-10 = 9.80 Hz               8.10    ppm     signal       1H   N--H amide                                  ______________________________________                                    

EXAMPLE 53,4,5,6,7,8-HEXAHYDRO-5-(2-ACETAMIDOETHYL)-2H-1-NAPHTHO-[2,1-b]PYRAN##STR33## Reactants: 5-(2-Acetamidoethyl)-2H-1-naphtho[2,1-b]pyran(Example 4): 2 mmol (5.34 mg)

Methanol: 25 cm³

Raney nickel: a few mg

Procedure:

The 5-(2-acetamidoethyl)-2H-1-naphtho[2,1-b]pyran is dissolved in themethanol, the Raney nickel is added and the reaction mixture is stirredunder a hydrogen atmosphere at ordinary pressure at room temperature forsix hours. The reaction mixture is filtered. The filtrate is evaporatedto dryness and the residue is recrystallized.

Characteristics:

Yield: 55%

Recrystallization solvent: toluene

Melting point: 117-118° C.

Molecular mass: 273.361 g.mol⁻¹ for C₁₇ H₂₃ NO₂

    ______________________________________                                        Microanalysis:                                                                            % C          % H    % N                                           ______________________________________                                        Calculated  74.68        8.48   5.12                                          Found       74.46        8.39   5.16                                          ______________________________________                                        Infrared:                                                                     3240           cm.sup.-1  ν N--H amide                                     2980-2800      cm.sup.-1  ν C--H alkyls                                    1610           cm.sup.-1  ν C═O amide                                  ______________________________________                                        NMR (d.sub.6 -DMSO) 80 MHz:                                                   1.30-2.15                                                                             ppm    unresolved peak                                                                           11H   H.sub.a, H.sub.c, H.sub.3, H.sub.6,                                           H.sub.7                                      2.35-2.80                                                                             ppm    unresolved peak                                                                            5H   H.sub.4, H.sub.5, H.sub.8                    3.20    ppm    multiplet    2H   H.sub.b                                      4.00    ppm    multiplet    2H   H.sub.2                                      6.50    ppm    doublet      1H   H.sub.10, J.sub.10-9  = 9.20 Hz              6.75    ppm    doublet      1H   H.sub.g, J.sub.9-10  = 9.20 Hz               7.90    ppm    signal       1H   N--H amide                                   ______________________________________                                    

EXAMPLE 6 3,4-DIHYDRO-5-(2-ACETAMIDOETHYL)-2H-1-NAPHTHO[2,1-b]PYRAN##STR34## Reactants: 5-(2-Acetamidoethyl)-2H-1-naphtho[2,1-b]pyran(Example 4): 2 mmol (534 mg)

Methanol: 80 cm³

Magnesium: 80 mmol (1.35 g)

Procedure:

The 5-(2-acetamidoethyl)-2H-1-naphtho[2,1-b]pyran is dissolved in themethanol and the reaction mixture is cooled using an ice/salt bath. Themagnesium is added in small portions and the reaction mixture is leftstirring at room temperature for 16 hours. 30 cm³ of a 6N hydrochloricacid solution are added little by little, with stirring. The reactionmixture is left to cool, is extracted with ether and the organic phaseis washed with water, dried over magnesium sulfate, filtered andevaporated to dryness.

Characteristics:

Yield: 42%

Recrystallization solvent: ether/petroleum ether

Melting point: 137-139° C.

Molecular mass: 291.849 g.mol⁻¹ for C₁₇ H₁₉ NO₂ +1.25H₂ O

    ______________________________________                                        Microanalysis:                                                                            % C          % H    % N                                           ______________________________________                                        Calculated  69.95        6.99   4.79                                          Found       70.00        6.63   4.75                                          ______________________________________                                        Infrared:                                                                     3240           cm.sup.-1  ν N--H amide                                     2980-2800      cm.sup.-1  ν C--H alkyls                                    1610           cm.sup.-1  ν C═O amide                                  ______________________________________                                        NMR (d.sub.6 -DMSO) 300 MHz:                                                  1.50-2.10                                                                             ppm    unresolved peak                                                                            5H   H.sub.3, H.sub.c                             3.10-3.85                                                                             ppm    unresolved peak                                                                            6H   H.sub.a, H.sub.b, H.sub.4                    3.95    ppm    multiplet    2H   H.sub.2                                      7.15-7.30                                                                             ppm    unresolved peak                                                                            3H   H.sub.6, H.sub.7, H.sub.10                   7.65    ppm    doublet      1H   H.sub.8, J.sub.8-7  = 7.45 Hz                7.80    ppm    doublet      1H   H.sub.9, J.sub.9-10  = 9.90 Hz               8.10    ppm    signal       1H   N--H                                         ______________________________________                                    

EXAMPLES 7 TO 114

By proceeding as in Examples 1 to 6, but by using the appropriatepreparations, the compounds of the following examples are obtained.

EXAMPLE 72,3-DIHYDRO-3-OXO-4-(2-PROPIONAMIDOETHYL)-1-NAPHTHO[2,1-b]-FURAN EXAMPLE8 2,3-DIHYDRO-3-OXO-4-(2-BUTYRAMIDOETHYL)-1-NAPHTHO[2,1-b]-FURAN EXAMPLE9 2,3-DIHYDRO-3-OXO-4-(2-ISOBUTYRAMIDOETHYL)-1-NAPHTHO[2,1-b]-FURANEXAMPLE 102,3-DIHYDRO-3-OXO-4-(2-TRIFLUOROACETAMIDOETHYL)-1-NAPHTHO[2,1-b]FURANEXAMPLE 11 2,3-DIHYDRO-3-OXO-4-(2-FORMAMIDOETHYL)-1-NAPHTHO[2,1-b]-FURANEXAMPLE 122,3-DIHYDRO-3-OXO-4-(2-PENTANAMIDOETHYL)-1-NAPHTHO[2,1-b]-FURAN EXAMPLE13 2,3-DIHYDRO-3-OXO-4-[2(IODOACETAMIDO)ETHYL]-1-NAPHTHO-[2,1-b]FURANEXAMPLE 142,3-DIHYDRO-3-OXO-4-[2-(CYCLOPROPANECARBOXAMIDO)ETHYL]-1-NAPHTHO[2,1-b]FURAEXAMPLE 152,3-DIHYDRO-3-OXO-4-[2-(CYCLOBUTANECARBOXAMIDO)ETHYL-]1-NAPHTHO[2,1-b]FURANEXAMPLE 162,3-DIHYDRO-3-OXO-4-[2-(CYCLOPENTANECARBOXAMIDO)ETHYL]-1-NAPHTHO[2,1-b]FURANEXAMPLE 172,3-DIHYDRO-3-OXO-4-[2-(CYCLOHEXANECARBOXAMIDO)ETHYL]-1-NAPHTHO[2,1-b]FURANEXAMPLE 182,3-DIHYDRO-3-OXO-4-[2-(PROPENE-1-CARBOXAMIDO)ETHYL]-1-NAPHTHO[2,1-b]FURANEXAMPLE 192,3-DIHYDRO-3-HYDROXY-4-(2-PROPIONAMIDOETHYL)-1-NAPHTHO-[2,1-b]FURANEXAMPLE 202,3-DIHYDRO-3-HYDROXY-(2-BUTYRAMIDOETHYL)-1-NAPHTHO-[2,1-b]FURAN EXAMPLE21 2,3-DIHYDRO-3-HYDROXY-4-(2-ISOBUTYRAMIDOETHYL)-1-NAPHTHO[2,1-b]FURANEXAMPLE 22 2,3-DIHYDRO-3-HYDROXY4(2-TRIFLUOROACETAMIDOETHYL)-1-NAPHTHO[2,1-b]FURAN EXAMPLE 232,3-DIHYDRO-3-HYDROXY 4(2-FORMAMIDOETHYL)-1-NAPHTHO-[2,1-b]FURAN EXAMPLE24 2,3-DIHYDRO-3-HYDROXY-4(2-PENTANAMIDOETHYL)-1-NAPHTHO-[2,1-b]FURANEXAMPLE 252,3-DIHYDRO-3-HYDROXY-4-[2-(IODOACETAMIDO)ETHYL]-1-NAPHTHO[2,1-b]FURANEXAMPLE 26 2,3-DIHYDRO-3-HYDROXY-4-[2-(CYCLOPROPANECARBOXAMIDO)ETHYL]-1-NAPHTHO[2,1-b]FURAN EXAMPLE 272,3-DIHYDRO-3-HYDROXY-4-[2-(CYCLOBUTANECARBOXAMIDO)ETHYL]-1-NAPHTHO[2,1-b]FURAN EXAMPLE 282,3-DIHYDRO-3-HYDROXY-4-[2-(CYCLOPENTANECARBOXAMIDO)ETHYL]-1-NAPHTHO[2,1-b]FURAN EXAMPLE 292,3-DIHYDRO-3-HYDROXY-4-[2-(CYCLOHEXANECARBOXAMIDO)ETHYL]-1-NAPHTHO[2,1-b]FURANEXAMPLE 302,3-DIHYDRO-3-HYDROXY-[2-(PROPENE-1-CARBOXAMIDO)ETHYL]-1-NAPHTHO[2,1-b]FURANEXAMPLE 31 4-(2-PROPIONAMIDOETHYL)-1-NAPHTHO[2,1-b]FURAN EXAMPLE 324-(2-BUTYRAMIDOETHYL)-1-NAPHTHO[2,1-b]FURAN EXAMPLE 334-(2-ISOBUTYRAMIDOETHYL)1-NAPHTHO[2,1-b]FURAN EXAMPLE 344-(2-TRIFLUOROACETAMIDOETHYL)-1-NAPHTHO[2,1-b]FURAN EXAMPLE 354-(2-FORMAMIDOETHYL)-1-NAPHTHO[2,1-b]FURAN EXAMPLE 364-(2-PENTANAMIDOETHYL)-1-NAPHTHO[2,1-b]FURAN EXAMPLE 374-[2-(IODOACETAMIDO)ETHYL]-1-NAPHTHO[2,1-b]FURAN EXAMPLE 384-[2-(CYCLOPROPANECARBOXAMIDO)ETHYL-]1-NAPHTHO[2,1-b]-FURAN EXAMPLE 394-[2-(CYCLOBUTANECARBOXAMIDO)ETHYL]-1-NAPHTHO[2,1-b]-FURAN EXAMPLE 404-[2-(CYCLOPENTANECARBOXAMIDO)ETHYL]-1-NAPHTHO[2,1-b]-FURAN EXAMPLE 414-[2-(CYCLOHEXANECARBOXAMIDO)ETHYL]-1-NAPHTHO[2,1-b]-FURAN EXAMPLE 424-[2-(PROPENE-1-CARBOXAMIDO)ETHYL]-1-NAPHTHO[2,1-b]FURAN EXAMPLE 435-(2-PROPIONAMIDOETHYL)-2H-1-NAPHTHO[2,1-b]PYRAN EXAMPLE 445-(2-BUTYRAMIDOETHYL)-2H-1-NAPHTHO[2,1-b]PYRAN EXAMPLE 455-(2-ISOBUTYRAMIDOETHYL)-2H-1-NAPHTHO[2,1-b]PYRAN EXAMPLE 465-(2-TRIFLUOROACETAMIDOETHYL)-2H-1-NAPHTHO[2,1-b]PYRAN EXAMPLE 47:5-(2-FORMAMIDOETHYL)-2H-1-NAPHTHO[2,1-b]PYRAN EXAMPLE 485-(2-PENTANAMIDOETHYL)-2H-1-NAPHTHO[2,1-b]PYRAN EXAMPLE 495-[2(IODOACETAMIDO)ETHYL]-2H-1-NAPHTHO[2,1-b]PYRAN EXAMPLE 505-[2-(CYCLOPROPANECARBOXAMIDO)ETHYL]-2H-1-NAPHTHO-[2,1-b]PYRAN EXAMPLE51 5-[2-(CYCLOBUTANECARBOXAMIDO)ETHYL]-2H-1-NAPHTHO[2,1-b]-PYRAN EXAMPLE52 5-[2-(CYCLOPENTANECARBOXAMIDO)ETHYL]-2H-1-NAPHTHO[2,1-b]-PYRANEXAMPLE 53 5-[2-(CYCLOHEXANECARBOXAMIDO)ETHYL]-2H-1-NAPHTHO[2,1-b]-PYRANEXAMPLE 54 5-[2-(PROPENE-1-CARBOXAMIDO)ETHYL]-2H-1-NAPHTHO[2, 1-b]-PYRANEXAMPLE 55 3,4,5,6,7,8-HEXAHYDRO-5-(2-PROPIONAMIDOETHYL)-2H-1NAPHTHO[2,1-b]PYRAN EXAMPLE 563,4,5,6,7,8-HEXAHYDRO-5-(2-BUTYRAMIDOETHYL)-2H-1-NAPHTHO-[2,1-b]PYRANEXAMPLE 57 3,4,5,6,7,8-HEXAHYDRO-5-(2-ISOBUTYRAMIDOETHYL)-2H-1NAPHTHO[2,1-b]PYRAN EXAMPLE 583,4,5,6,7,8-HEXAHYDRO-5-(2-TRIFLUOROACETAMIDOETHYL)-2H-1-NAPHTHO[2,1-b]PYRANEXAMPLE 593,4,5,6,7,8-HEXAHYDRO-5-(2-FORMAMIDOETHYL)-2H-1-NAPHTHO-[2,1-b]PYRANEXAMPLE 603,4,5,6,7,8-HEXAHYDRO-5-(2-PENTANAMIDOETHYL)-2H-1-NAPHTHO-[2,1-b]PYRANEXAMPLE 613,4,5,6,7,8-HEXAHYDRO-5-[2-(IODOACETAMIDO)ETHYL]-2H-1-NAPHTHO[2,1-b]PYRANEXAMPLE 623,4,5,6,7,8-HEXAHYDRO-5-[2-(CYCLOPROPANECARBOXAMIDO)ETHYL]-2H-1-NAPHTHO[2,1-b]PYRANEXAMPLE 633,4,5,6,7,8-HEXAHYDRO-5-[2-(CYCLOBUTANECARBOXAMIDO)ETHYL]-2H-1-NAPHTHO[2,1-b]PYRANEXAMPLE 643,4,5,6,7,8-HEXAHYDRO-5-[2-(CYCLOPENTANECARBOXAMIDO)ETHYL]-2H-1-NAPHTHO[2,1-b]PYRANEXAMPLE 653,4,5,6,7,8-HEXAHYDRO-5-[2-(CYCLOHEXANECARBOXAMIDO)ETHYL]-2H-1-NAPHTHO[2,1-b]PYRANEXAMPLE 663,4,5,6,7,8-HEXAHYDRO-5-[2-(PROPENE-1-CARBOXAMIDO)ETHYL]-2H-1-NAPHTHO[2,1-b]PYRANEXAMPLE 67 3,4-DIHYDRO-5-(2-PROPIONAMIDOETHYL)-2H-1-NAPHTHO[2,1-b]-PYRANEXAMPLE 68 3,4-DIHYDRO-5-(2-BUTYRAMIDOETHYL)-2H-1-NAPHTHO[2,1-b]PYRANEXAMPLE 69 3,4-DIHYDRO-5-(2-ISOBUTYRAMIDOETHYL)-2H-1-NAPHTHO[2,-b]-PYRANEXAMPLE 703,4-DIHYDRO-5-(2-TRIFLUOROACETAMIDOETHYL)-2H-1-NAPHTHO-[2,1-b]PYRANEXAMPLE 71 3,4-DIHYDRO-5-(2-FORMAMIDOETHYL)-2H-1-NAPHTHO[2,1-b]PYRANEXAMPLE 72 3,4-DIHYDRO-5-(2-PENTANAMIDOETHYL)-2H-1-NAPHTHO[2,1-b]-PYRANEXAMPLE 733,4-DIHYDRO-5-[2-(IODOACETAMIDO)ETHYL]-2H-1-NAPHTHO[2,1-b]-PYRAN EXAMPLE743,4-DIHYDRO-5-[2-(CYCLOPROPANECARBOXAMIDO)ETHYL]-2H-1-NAPHTHO[2,1-b]PYRANEXAMPLE 753,4-DIHYDRO-5-[2-(CYCLOBUTANECARBOXAMIDO)ETHYL]-2H-1-NAPHTHO[2,1-b]PYRANEXAMPLE 763,4-DIHYDRO-5-[2-(CYCLOPENTANECARBOXAMIDO)ETHYL]-2H-1-NAPHTHO[2,1-b]PYRANEXAMPLE 773,4-DIHYDRO-5-[2-(CYCLOHEXANECARBOXAMIDO)ETHYL]-2H-1-NAPHTHO[2,1-b]PYRANEXAMPLE 783,4-DIHYDRO-5-[2-(PROPENE-1-CARBOXAMIDO)ETHYL]-2H-1-NAPHTHO[2,1-b]PYRANEXAMPLE 79N-[2-(2,3-DIHYDRO-3-OXO-1-NAPHTHO[2,1-b]FURAN-4YL)ETHYL]-N'-METHYLUREAEXAMPLE 80 N-[2-(2,3-DIHYDRO-3-OXO-1-NAPHTHO[2,1-b]FURAN-4-YL)ETHYL]-N'-ETHYLUREA EXAMPLE 81N-[2-(2,3-DIHYDRO-3-OXO-1-NAPHTHO[2,1-b]FURAN-4YL)ETHYL]-N'-n-PROPYLUREAEXAMPLE 82N-[2-(2,3-DIHYDRO-3-OXO-1-NAPHTHO[2,1-b]FURAN-4-YL)ETHYL]-N'-CYCLOPROPYLUREAEXAMPLE 83N-[2-(2,3-DIHYDRO-3-OXO-1-NAPHTHO[2,1-b]FURAN-4-YL)ETHYL]-N'-n-PROPYLTHIOUREAEXAMPLE 84N-[2-(2,3-DIHYDRO-3-OXO-1-NAPHTHO[2,1-b]FURAN-4-YL)ETHYL]-N'-CYCLOPROPYLTHIOUREAEXAMPLE 85N-[2-(2,3-DIHYDRO-3-HYDROXY-1-NAPHTHO[2,1-b]FURAN-4-YLETHYL]-N'-METHYLUREAEXAMPLE 86N-[2-(2,3-DIHYDRO-3-HYDROXY-1-NAPHTHO[2,1-b]FURAN-4-YL)ETHYL]-N'-ETHYLUREAEXAMPLE 87 N-[2-(2,3-DIHYDRO-3-HYDROXY-1-NAPHTHO[2,1-b]FURANYL)ETHYL]-N'-PROPYLUREA EXAMPLE 88N-[2-(2,3-DIHYDRO-3-HYDROXY-1-NAPHTHO[2,1-b]FURAN-4YL)ETHYL]-N'-CYCLOPROPYLUREAEXAMPLE 89N-[2-(2,3-DIHYDRO-3-HYDROXY-1-NAPHTHO[2,1-b]FURAN-4-YL)ETHYL]-N'-PROPYLTHIOUREAEXAMPLE 90N-[2-(2,3-DIHYDRO-3-HYDROXY-1-NAPHTHO[2,1-b]FURAN-4-YL)ETHYL]-N'-CYCLOPROPYLTHIOUREAEXAMPLE 91 N-[2-(1-NAPHTHO[2,1-b]FURAN-4-YL)ETHYL]-N'-METHYLUREA EXAMPLE92 N-[2-(1-NAPHTHO[2,1-b]FURAN-4-YL)ETHYL]-N'-ETHYLUREA EXAMPLE 93N-[2-(1-NAPHTHO[2,1-b]FURAN-4-YL)ETHYL]-N'-PROPYLUREA EXAMPLE 94N-[2-(1-NAPHTHO[2,1-b]FURAN-4-YL)ETHYL]-N'-CYCLOPROPYLUREA EXAMPLE 95N-[2-(1-NAPHTHO[2,1-b]FURAN-4-YL)ETHYL]-N'-PROPYLTHIOUREA EXAMPLE 96N-[2-(1-NAPHTHO[2,1-b]FURAN-4-YL)ETHYL]-N'-CYCLOPROPYLTHIOUREA EXAMPLE97 N-[2-(2H-1-NAPHTHO[2,1-b]PYRAN-5-YL)ETHYL]-N'-METHYLUREA EXAMPLE 98N-[2-(2H-1-NAPHTHO[2,1-b]PYRAN-5-YL)ETHYL]-N'-ETHYLUREA EXAMPLE 99N-[2-(2H-1-NAPHTHO[2,1-b]PYRAN-5-YL)ETHYL]-N'-n-PROPYLUREA EXAMPLE 100N-[2-(2H-1-NAPHTHO[2,1-b]PYRAN-5-YL)ETHYL]-N'-CYCLOPROPYLUREA EXAMPLE101 N-[2-(2H-1-NAPHTHO[2,1-b]PYRAN-5-YL)ETHYL]-N'-PROPYLTHIOUREA EXAMPLE102 N-[2-(2H-1-NAPHTHO[2,1-b]PYRAN-5-YL)ETHYL]-N'-CYCLOPROPYLTHIOUREAEXAMPLE 103N-[2-(3,4,5,6,7,8-HEXAHYDRO-2H-1-NAPHTHO[2,1-b]PYRAN-5-YL)ETHYL]-N'-METHYLUREAEXAMPLE 104N-[2-(3,4,5,6,7,8-HEXAHYDRO-2H-1-NAPHTHO[2,1-b]PYRAN-5-YL)ETHYL]-N'-ETHYLUREAEXAMPLE 105N-[2-(3,4,5,6,7,8-HEXAHYDRO-2H-1-NAPHTHO[2,1-b]PYRAN-5-YL)ETHYL]-N'-PROPYLUREAEXAMPLE 106N-[2-(3,4,5,6,7,8-HEXAHYDRO-2H-1-NAPHTHO[2,1-b]PYRAN-5-YL)ETHYL]-N'-CYCLOPROPYLUREAEXAMPLE 107N-[2-(3,4,5,6,7,8-HEXAHYDRO-2H-1-NAPHTHO[2,1-b]PYRAN-5-YL)ETHYL]-N'-PROPYLTHIOUREAEXAMPLE 108N-[2-(3,4,5,6,7,8-HEXAHYDRO-2H-1-NAPHTHO[2,1-b]PYRAN-5-YL)ETHYL]-N'-CYCLOPROPYLTHIOUREAEXAMPLE 109N-[2-(3,4-DIHYDRO-2H-1-NAPHTHO[2,1-b]PYRAN-5-YL)ETHYL]-N'-METHYLUREAEXAMPLE 110N-[2-(3,4-DIHYDRO-2H-1-NAPHTHO[2,1-b]PYRAN-5-YL)ETHYL]-N'-ETHYLUREAEXAMPLE 111N-[2-(3,4-DIHYDRO-2H-1-NAPHTHO[2,1-b]PYRAN-5-YL)ETHYL]-N'-PROPYLUREAEXAMPLE 112N-[2-(3,4-DIHYDRO-2H-1-NAPHTHO[2,1-b]PYRAN-5-YL)ETHYL]-N'-CYCLOPROPYLUREAEXAMPLE 113N-[2-(3,4-DIHYDRO-2H-1-NAPHTHO[2,1-b]PYRAN-5-YL)ETHYL]-N'-PROPYLTHIOUREAEXAMPLE 114 N-[2-(3,4-DIHYDRO-2H-1-NAPHTHO[2,1-b]PYRAN-5-YL)ETHYL]-N'-CYCLOPROPYLTHIOUREA EXAMPLE 115N-[2-(7H-8,9-DIHYDROPYRANO[3,2-e]INDOLYL)ETHYL]ACETAMIDE ##STR35## Byproceeding on the compound of Preparation 39 with acetyl chloride, thetitle compound is obtained. EXAMPLES 116 TO 118

By proceeding as in Example 115, but using the appropriate acylchloride, the compounds of the following examples are obtained:

EXAMPLE 116 N-[2-(7H-8,9-DIHYDROPYRANO[3,2-e]INDOLYL)ETHYL]-PROPIONAMIDEEXAMPLE 117N-[2-(7H-8,9-DIHYDROPYRANO[3,2-e]INDOLYL)ETHYL]CYCLOPROPANECARBOXAMIDEEXAMPLE 118N-[2-(7H-8,9-DIHYDROPYRANO[3,2-e]INDOLYL)ETHYL]CYCLOBUTANECARBOXAMIDEEXAMPLE 1192,3-DIHYDRO-2-METHYL-4-(2-ACETAMIDOETHYL)1-NAPHTHO[2,1-b]-FURAN##STR36## Reactants: N-[2-(8-Allyl-7-hydroxynaphth-1-yl)ethyl]acetamide(Preparation 40): 3.7 mmol (1 g)

Trifluoroacetic acid (99%, d=1.48): 32 mmol (2.33 cm³)

Procedure:

The compound from Preparation 40 is dissolved in the trifluoroaceticacid in a 50 cm³ flask and the mixture is brought to reflux for 8 h. Itis left to cool. The medium is evaporated to dryness and the residue istaken up in water and extracted with ethyl acetate (3×10 cm³). Theorganic phase is washed with 2×2 cm³ of a 10% aqueous sodium hydroxidesolution and then with water. The organic phase is dried over MgSO₄ andbrought to dryness. The product is purified on a silica column usingacetone/toluene/cyclohexane as eluent.

Characteristics:

Molecular mass: 269.34 g for C₁₇ H₁₉ NO₂

Appearance: whitish solid

Melting point: 136° C.

R_(f) : 0.32 eluent: acetone/toluene/cyclohexane (4/4/2)

Yield: 73%

Recrystallization solvent: toluene/cyclohexane (1/3)

    ______________________________________                                        Infrared:                                                                     3240 and 3050  cm.sup.-1  ν NH amide                                       2960-2840      cm.sup.-1  ν CH alkyls                                      1630           cm.sup.-1  ν CO amide                                       1000-1580      cm.sup.-1  ν C═C aromatics                              ______________________________________                                        NMR (CDCl.sub.3, δ) 300 MHz:                                            1.54   ppm doublet   3H    H.sub.a,                                                                             J.sub.a-b  = 6.30 Hz                        1.96   ppm singlet   3H    H.sub.g                                            3.29   ppm multiplet 2H    H.sub.d                                            3.40   ppm double doublet                                                                          1H    H.sub.c "cis"                                                                        J = 7.6 Hz; J.sub.c'-b  =                                                     7,7 Hz;                                                                       J.sub.c'-c  = 15,2 Hz                       3.56   ppm multiplet 2H    H.sub.e                                            3.94   ppm double doublet                                                                          1H    H.sub.c "trans"                                                                      J = 9.2 Hz; J.sub.c'-c  =                                                     15,2 Hz                                     5.05-5.07                                                                            ppm unresolved peak                                                                         1H    H.sub.b                                            5.53   ppm signal    1H    H.sub.f                                            7.08-7.23                                                                            ppm unresolved peak                                                                         3H    H, aromatic protons, H.sub.5, H.sub.6,                                        H.sub.9                                            7.67-7.70                                                                            ppm unresolved peak                                                                         2H    H, aromatic protons, H.sub.8,                      ______________________________________                                                                   H.sub.7                                        

EXAMPLE 120N-[2-(2,3-DIHYDRO-2-METHYL-1-NAPHTHO[2,1-b]FURAN-4-YL)ETHYL]-N'-METHYLUREA

By proceeding as in Example 119, but using the compound from Preparation41 at the start, the title product is obtained.

Melting point: 165-169° C.

EXAMPLES 121 TO 130 EXAMPLE 121N-[2-(7H-8,9-DIHYDROTHIENO[3,2-f]BENZOTHIOPYRAN-1-YL)ETHYL]-ACETAMIDE##STR37## EXAMPLE 122N-[2-(7H-8,9-DIHYDRO-THIENO[3,2-f]BENZOPYRAN-1-YL)ETHYL]-PROPIONAMIDEEXAMPLE 123N-[2-(7H-8,9-DIHYDRO-THIENO[3,2-f]BENZOPYRAN-1-YL)ETHYL]-CYCLOPROPANECARBOXAMIDEEXAMPLE 124N-[2-(7H-8,9-DIHYDRO-THIENO[3,2-f]BENZOPYRAN-1-YL)ETHYL]-CYCLOBUTANECARBOXAMIDEEXAMPLE 125N-[2-(7H-8,9-DIHYDRO-THIENO[3,2-f]BENZOPYRAN-1-YL)ETHYL]-TRIFLUOROACETAMIDEEXAMPLE 126N-[2-(7H-8,9-DIHYDRO-FURO[3,2-f]BENZOPYRAN-1-YL)ETHYL]-ACETAMIDE##STR38## EXAMPLE 127N-[2-(7H-8,9-DIHYDROFURO[3,2-f]BENZOPYRAN-1-YL)ETHYL]-PROPIONAMIDEEXAMPLE 128N-[2-(7H-8,9-DIHYDROFURO[3,2-f]BENZOPYRAN-1-YL)ETHYL]-CYCLOPROPANECARBOXAMIDEEXAMPLE 129N-[2-(7H-8,9-DIHYDROFURO[3,2-f]BENZOPYRAN-1-YL)ETHYL]-CYCLOBUTANECARBOXAMIDEXAMPLE 130N-[2-(7H-8,9-DIHYDROFURO[3,2-f]BENZOPYRAN-1-YL)ETHYL]-TRIFLUOROACETAMIDEPREPARATION 42 2-(8,9-Dihydro-7H-furo[3,2-f]chromen-1-yl)ethylamine

Stage A: 5-Methoxy-2,3-dihydrobenzo[b]furan-3-one

Under inert atmosphere, 0.08 mol (1.85 g) of metallic sodium aredissolved in 80 ml of anhydrous methanol. When all sodium is dissolved,the methanol is evaporated and the sodium methanolate thus obtained isdissolved in 300 ml of anhydrous toluene, then 80 mmol (20 g) of methyl5-methoxy-2-(2-methoxy-2-oxoetoxy) benzoate are added. The reactionmixture is refluxed 35 minutes. The toluene is evaporated and theresidue is dissolved in water. The solution is acidified withconcentrated chlorhydric acid until pH=1, and the precipitate isfiltered. The solid thus obtained is dissolved in 300 ml of methanol and200 ml of NaOH 30% are added, and the mixture is refluxed 5 hours. Aftercooling, the methanol is evaporated and the mixture diluted with waterand acidified with concentrated chlorhydric acid until pH=1. The redprecipitate thus obtained is filtered, washed with water andrecrystallized in water/ethanol.

MP=92° C.

Stage B: 2-(5-Methoxybenzo[b]furan-3-yl)acetonitrile

Under inert atmosphere, 83 mmol of sodium hydride are suspended in 100ml of anhydrous THF. The temperature is cooled at -15° C. and 83 mmol(14.7 g) of (EtO)₂ POCH₂ CN in 50 ml of 1BF are dropply added. Then 55mmol (9 g) of compound obtained in stage A in 100 ml of THF aredropwised at -15° C. The solution is stirred during 2 hours at thattemperature before being hydrolysed. The mixture is extracted with ethylacetate and the organic layers are washed with brine, dried overmagnesium sulfate and concentrated. The title product is obtained afterpurification by chromatography on silica gel.

Stage C: 2-[5-(Hydroxybenzo[b]furan-3-yl)acetonitrile

Under inert atmosphere, 38 mmol (7.1 g) of compound obtained in stage Bare dissolved in 140 ml of CH₂ Cl₂. The mixture is cooled with an icebath and 76 mmol (7.3 ml) of BBr₃ are added. The reaction mixture isstirred at room temperature 5 hours, then hydrolysed with ice/water andextrated with CH₂ Cl₂. The organic layer is washed with water, dried onmagnesium sulfate and concentrated to yield the title product.

MP=110° C.

Stage D: 2-[5-(Cyanomethoxy)benzo[b]furan-3-yl]acetonitrile

To a solution of 33 mmol of phenol obtained in stage C in 150 ml ofacetone are added 100 mmol (13.8 g) of potassium carbonate. The mixtureis refluxed 15 minutes and 100 mmol (8.9 ml) of propargyl bromide areadded. The reaction is refluxed overnight. After cooling, the reactionmixture is filtered and the filtrate is concentrated. The residue isdissolved in a mixture of water/ethylacetate and after extraction, theorganic layers are washed successively by NaOH 10% and brine, dried overmagnesium sulfate and concentrated. The title product is obtained bychromatography on silica gel.

MP=86-87° C.

Stage E: 2-(7H-Furo[3,2-f]chromen-1-yl]acetonitrile

A mixture of 0.03 mol (6 g) of compound obtained in stage D in 170 ml oftriethyleneglycol is refluxed 5 minutes. The reaction is then cooled atroom temperature and hydrolysed by a mixture water/ice. The precipitatethus formed is filtrated and recrystallized in isopropanol to yield thetitle product.

MP=99-101° C.

Stage F: 2-(8,9-Dihydro-7H-furo[3,2-f]chromen-1-yl)ethylamine

1.4 mmol of compound obtained in stage E are dissolved in 30 ml ofethanol saturated with ammonia, in the presence of 400 mg of Nickel(Raney). The reaction mixture is stirred at 50° C. under 50 atm ofhydrogen during 5 hours. After cooling and filtration of the catalyst,the filtrate is concentrated, dissolved in a mixture of ether/water andextracted. The organic layer is dried over magnesium sulfate andconcentrated to yield the title product.

MP (HCl)=160° C.

PREPARATION 43 2-(8,9-Dihydro-7H-thieno[3,2-f]chromen-1-yl)ethylamine

The procedure is the same as that of Preparation 42 using as startingmaterial methyl 5-methoxy-2-[(2-methoxy-2-oxoethyl)thio]benzoate.

PREPARATION 44 2-(3,7,8,9-Tetrahydropyrano[3,2-e]indol-1-yl)ethylamine

The procedure is the same as that of Preparation 42 using as startingmaterial methyl 5-methoxy-2-[(2-methoxy-2-oxoethyl)amino]benzoate.

PREPARATION 45 N-{2-[5-(Cyanomethoxy)benzo[b]furan-3-yl]ethyl}acetamide

Stage A: N-[2-(5-Methoxybenzo[b]furan-3-yl)ethyl]acetamide

A solution of 18.7 mmol (3.5 g) of compound obtained in stage B ofPreparation 42 in 80 ml of acetic anhydride is stirred under 60 atm ofhydrogen at 60° C., with 0.4 g of Nickel (Raney) during 6 hours. Aftercooling, the catalyst is filtered and rinsed with ethanol. The filtrateis concentrated and dissolved in ethyl acetate and stirred into NaOH 30%during 30 minutes. After extraction, the organic layer is washed withbrine, dried over magnesium sulfate and concentrated. The title productis recrystallized in toluene.

MP=113° C.

Stage B: N-[2-(5-Hydroxybenzo[b]furan-3-yl)ethyl]acetamide

The procedure is the same as that used in stage C of Preparation 42.

MP=115° C.

Stage C: N-{2-[5-(Cyanomethoxy)benzo[b]furan-3-yl]ethyl}acetamide

To a solution of 4.1 mmol of compound obtained in stage B in 30 ml ofacetone are added 12.3 mmol (1.7 g) of potassium carbonate, and themixture is warmed to reflux during 15 minutes. Propargyl bromide (12.5mmol, 1.35 ml) is added and the reaction is refluxed during 6 hours.After cooling, the mixture is filtrated and the filtrate concentrated.The residue thus obtained is dissolved in ethyl acetate, washed withwater, then with NaOHIM, and with brine. The organic layer is dried overmagnesium sulfate, concentrated and the solid obtained recrystallized intoluene/cyclohexane to yield the title product.

MP=72-73° C.

PREPARATION 46 N-[2-(4-Allyl-5-hydroxybenzo[b]furan-3-yl)ethyl]acetamide

The procedure is the same as that used in stages C and D of Preparation40 from the compound obtained in stage B of Preparation 45.

PREPARATION 47N-[2-(5-Carboxymethyloxybenzo[b]furan-3-yl)ethyl]acetamide

The procedure is the same as that used in Preparation 1 from thecompound obtained in stage B of Preparation 45.

EXAMPLE 131 N-[2-(8,9-Dihydro-7H-furo[3,2-f]chromen-1-yl)ethyl]acetamide

To a solution of 0.67 mmol of the hydrochloride of the amine obtained inPreparation 42 in 18 ml of chloroform and 6 ml of water are added 1.5mmol of potassium carbonate and 0.84 mmol of acetylchloride. The mixtureis stirred vigorously for 30 minutes, then extracted. The organic layeris dried over magnesium sulfate and concentrated to yield the titleproduct.

MP=162° C.

    ______________________________________                                        Microanalysis:                                                                            C        H         N                                              ______________________________________                                        % Calculated  69.48      6.61      5.40                                       % Found       69.62      6.30      5.24                                       ______________________________________                                    

The compounds of Examples 132 to 139 are obtained using the sameprocedure as in Example 131 and the appropriate acid chloride.

EXAMPLE 132N-[2-(8,9-Dihydro-7H-furo[3,2-f]chromen-1-yl)ethyl]propanamide EXAMPLE133 N-[2-(8,9-Dihydro-7H-furo[3,2-f]chromen-1-yl)ethyl]-1-cyclopropanecarboxamide EXAMPLE 134N-[2-(8,9-Dihydro-7H-furo[3,2-f]chromen-1-yl)ethyl]-1-cyclobutanecarboxamide EXAMPLE 135N-[2-(8,9-Dihydro-7H-furo[3,2-f]chromen-1-yl)ethyl]-2,2,2-trifluoroacetamidEXAMPLE 136N-[2-(8,9-Dihydro-7H-furo[3,2-f]chromen-1-yl)ethyl]acrylamide

MP=104-106° C.

EXAMPLE 137N-[2-(8,9-Dihydro-7H-furo[3,2-f]chromen-1-yl)ethyl]-2-iodoacetamide

MP=131° C.

EXAMPLE 138 N-[2-(8,9-Dihydro7H-furo[3,2-f]chromen-1-yl)ethyl]-2-butenamide

MP=137° C.

EXAMPLE 139N-[2-(8,9-Dihydro-7H-furo[3,2-f]chromen-1-yl)ethyl]-3-butenamide

MP=104° C.

Examples 140 to 144 are prepared using the same procedure as in Example131, from the compound obtained in Preparation 43 and the appropriateacid chloride.

EXAMPLE 140N-[2-(8,9-Dihydro-7H-thieno[3,2-f]chromen-1-yl)ethyl]acetamide EXAMPLE141 N-[2-(8,9-Dihydro-7H-thieno[3,2-f]chromen-1-yl)ethyl]propanamideEXAMPLE 142N-[2-(8,9-Dihydro-7H-thieno[3,2-f]chromen-1-yl)ethyl]-1-cyclopropanecarboxamide EXAMPLE 143N-[2-(8,9-Dihydro-7H-thieno[3,2-f]chromen-1-yl)ethyl]-1-cyclobutanecarboxamide EXAMPLE 144N-[2-(8,9-Dihydro-7H-thieno[3,2-f]chromen-1-yl)ethyl]-2,2,2-trifluoroacetamide

Examples 145 to 148 are prepared using the same procedure as in Example131, from the compound obtained in Preparation 44 and the appropriateacid chloride.

EXAMPLE 145N-[2-(3,7,8,9-Tetrahydropyrano[3,2-e]indol-1-yl)ethyl]acetamide EXAMPLE146 N-[2-(3,7,8,9-Tetrahydropyrano[3,2-e]indol-1-yl)ethyl]propanamideEXAMPLE 147N-[2-(3,7,8,9-Tetrahydropyrano[3,2-e]indol-1-yl)ethyl]-1-cyclopropanecarboxamide EXAMPLE 148N-[2-(3,7,8,9-Tetrahydropyrano[3,2-e]indol-1-yl)ethyl]-1-cyclobutanecarboxamide EXAMPLE 149N-[12-(8,9-Dihydro-7H-furo[3,2-f]chromen-1-yl)ethyl]N-methylacetamide

The compound obtained in Example 131 is treated with sodium hydride andmethyl iodide to yield the title product.

MP=82° C.

EXAMPLE 150 N-[2-(7H-Furo[3,2-f]chromen-1-yl)ethyl]acetamide

A solution of 1.95 mmol of the compound obtained in Preparation 45 in 20ml of triethylene glycol is warmed to 280° C. during 16 minutes. Aftercooling, the mixture is dissolved in water and ethylacetate andextracted with ethylacetate. The organic layer is washed with brine,dried over magnesium sulfate, concentrated and purified bychromatography on silica gel.

MP=129° C.

    ______________________________________                                        Microanalysis                                                                             C        H         N                                              ______________________________________                                        % Calculated  70.02      5.87      5.44                                       % Found       69.82      6.10      5.54                                       ______________________________________                                    

EXAMPLE 151N-[2-(7-Oxo-7,8-dihydrofuro[3',2':3,4]benzo[b]furan-1-yl)ethyl]acetamide

The procedure is the same as that used in Example 1 from the compoundobtained in Preparation 47.

EXAMPLE 152N-[2-(7-Hydroxy-7,8-dihydrofuro[3',2':3,4]benzo[b]furan-1-yl)ethyl]acetamid

The procedure is the same as that used in Example 2 from the compoundobtained in Example 151.

EXAMPLE 153N-[2-(7-Methyl-7,8-dihydrofuro[3',2':3,4]benzo[b]furan-1-yl)ethyl]acetamide

The procedure is the same as that used in Example 119 from the compoundobtained in Preparation 46.

EXAMPLE 154N-[2-(8,9-Dihydro-7H-furo[3,2-chromen-1-yl)ethyl]-N'-methylurea

To a suspension of 0.01 mole of2-(8,9-dihydro-7H-furo[3,2-f]chromen-1-yl)ethylamine hydrochloride infive (5) ml of pyridine, 0.011 mole of methylisocyanate is addeddropwise with stirring. The reaction mixture is stirred for one (1) hourat 80° C., then poured on ice/water. After classical work up andpurification, the title compound is obtained.

Examples 155 to 158 are obtained using the same procedure as in Example154.

EXAMPLE 155N-[2-(8,9-Dihydro-7H-furo[3,2-f]chromen-1-yl)ethyl]-N'-isopropylurea

This compound is prepared by reacting the compound of Preparation 42(hydrochloride) and isopropyl isocyanate.

EXAMPLE 156N-Cyclobutyl-N'-[2-(8,9-dihydro-7H-furo[3,2-f]chromen-1-yl)ethyl]urea

This compound is prepared by reacting the compound of Preparation 42(hydrochloride) and cyclobutyl isocyanate.

EXAMPLE 157N-[2-(8,9-Dihydro-7H-thieno(3,2-f]chromen-1-yl)ethyl]-N'-methylurea

This compound is prepared by reacting the compound of Preparation 43(hydrochloride) and methyl isocyanate.

EXAMPLE 158N-Methyl-N'-[2-(3,7,8,9-tetrahydropyrano[3,2-f]indol-1-yl)ethyl]urea

This compound is prepared by reacting the compound of Preparation 44(hydrochloride) and methyl isocyanate.

It is to be noted that Examples 131, 132, 133, 134, and 135 yield theidentical products as Examples 126, 127, 128, 129, and 130, and thatExamples 140, 141, 142, 143, 144, 145, 146, 147, and 148 yield theidentical products as Examples 121, 122, 123, 124, 125, 115, 116, 117,and 118, although the nomenclature employed for naming of the saidproducts is different.

EXAMPLE 159N-[2-(8,9-Dihydro-7H-furo[3,2-f]chromen-1-yl)ethyl]-N'-propylurea:MP=165° C.

This compound is prepared according to the procedure of Example 154 byreacting the compound of Preparation 42 as its hydrochloride withpropylisocyanate.

EXAMPLE 160N-Butyl-N'-[2-(8,9-dihydro-7H-furo[3,2-f]chromen-1-yl)ethyl)urea:MP=132-133° C.

This compound is prepared according to the procedure of Example 154 byreacting the compound of Preparation 42 as its hydrochloride withbutylisocyanate.

EXAMPLE 161N-Cyclopropyl-N'-[2-(8,9-dihydro-7H-furo[3,2-f]chromen-1-yl)ethyl]thiourea:MP=160-161° C.

This compound is prepared according to the procedure of Example 154 byreacting the compound of Preparation 42 as its hydrochloride withcyclopropylisocyanate.

EXAMPLE 162N-[2-(8,9-Dihydro-7H-furo[3,2-f]chromen-1-yl)ethyl]-N'-propylthiourea:MP=100° C.

This compound is prepared according to the procedure of Example 154 byreacting the compound of Preparation 42 as its hydrochloride withpropylisothiocyanate.

EXAMPLE 163N-Butyl-N'-[2-(8,9-dihydro-7H-furo[3,2-f]chromen-1-yl)ethyl]thiourea:MP=121-122° C.

This compound is prepared according to the procedure of Example 154 byreacting the compound of Preparation 42 as its hydrochloride withbutylisothiocyanate.

PHARMACOLOGICAL STUDY EXAMPLE A Study of the Acute Toxicity

The acute toxicity was assessed after oral administration to batches of8 mice (26±2 grams). The animals were observed at regular intervalsduring the first day and daily during the two weeks following thetreatment. The LD₅₀, resulting in the death of 50% of the animals, wasevaluated.

The LD₅₀ of the products tested is greater than 1000 mg.kg⁻¹ for thecompounds studied, which indicates the low toxicity of the compounds ofthe invention.

EXAMPLE B Study of the Binding to Melatonin Receptors

B1) Study on Sheep Pars Tuberalis Cells

Studies of the binding of the compounds of the invention to melatoninreceptors were carried out according to conventional techniques on sheeppars tuberalis cells. The pars tuberalis of the adenohypophysis is infact characterized, in mammals, by a high density of melatonin receptors(Journal of Neuroendocrinology, 1, pp 1-4, 1989).

Protocol

1) Sheep pars tuberalis membranes are prepared and used as target tissuein saturation experiments in order to determine the binding capacitiesand affinities for 2-(¹²⁵ I) iodomelatonin.

2) Sheep pars tuberalis membranes are used as target tissue, with thevarious compounds to be tested, in competitive binding experiments withrespect to 2-iodo-melatonin.

Each experiment is carried out in triplicate and a range of differentconcentrations is tested for each compound.

The results make it possible to determine, after statistical treatment,the binding affinities of the compound tested.

Results

It appears that the compounds of the invention have a very high affinityfor melatonin receptors. In particular, the compound of Example 119 hasan extremely powerful affinity for melatonin receptors, with an IC₅₀ of6.9×10⁻¹⁵ M.

B2) Study on Chicken Brain Cell Membranes (Gallus domesticus)

The animals used are 12-day old chickens (Gallus domesticus). They aresacrificed between 1300 and 1700 hours on the day of their arrival. Thebrains are quickly removed and frozen at -200° C. and then stored at-80° C. The membranes are prepared according to the method described byYuan and Pang (Journal of Endocrinology, 128. pages 475-482, 1991).2-(¹²⁵ I)Iodomelatonin is incubated in the presence of the membranes ina buffered solution at pH 7.4 for 60 min at 25° C. At the end of thisperiod, the membrane suspension is filtered (Whatman GF/C). Theradioactivity retained on the filter is determined using a Beckman® LS6000 liquid scintillation counter.

The products used are:

2-(¹²⁵ I)iodomelatonin

melatonin

compounds of the invention

In primary screening, the molecules are tested at 2 concentrations (10⁻⁷and 10⁻⁵ M). Each result is the mean of 3 independent measurements. Theactive molecules retained after the results of the primary screeningwere made the subject of a quantitative determination of theirefficiency (IC₅₀). They are used at 10 different concentrations.

Thus, the IC₅₀ values found for the preferred compounds of theinvention, which correspond to the values of the affinity, show that thebinding of the compounds tested is very powerful.

EXAMPLE C Four Plates Test

The products of the invention are administered via the esophagus tobatches of ten mice. One batch receives acacia syrup. 30 minutes afteradministration of the test products, the animals are placed incompartments, the floor of which comprises four metal plates. Every timethe animal passes from one plate to another, it receives a mild electricshock (0.35 mA). The number of transfers from one plate to another isrecorded during one minute. After administration, the compounds of theinvention significantly increase the number of transfers from one plateto another, demonstrating the anxiolytic activity of the compounds ofthe invention.

EXAMPLE D Compounds of the Invention on the Circadian Rhythms of RatLocomotory Activity

The involvement of melatonin in controlling, by day/night alternation,the majority of the physiological, biochemical and behavioral circadianrhythms has made it possible to establish a pharmacological model forresearching melatoninergic ligands.

The effects of the molecules are tested on many parameters and inparticular on the circadian rhythms of locomotory activity whichrepresent a reliable marker for the activity of the endogenous circadianclock.

In this study, the effects of these molecules on a specific experimentalmodel, namely the rat placed in temporal isolation (permanent darkness),were evaluated.

Protocol

Male Long Evans rats, aged one month, are subjected, from their arrivalin the laboratory, to a light cycle of 12 h of light per 24 h (LD12:12).

After adapting for 2 to 3 weeks, they are placed in cages equipped witha wheel connected to a recording system in order to detect the phases oflocomotory activity and thus to monitor the nyctohemeral (LD) orcircadian (DD) rhythms.

As soon as the rhythms recorded testify to stable control by the lightcycle LD 12:12, the rats are placed in permanent darkness (DD).

Two to three weeks later, when the free mode (rhythm reflecting that ofthe endogenous clock) is clearly established, the rats receive a dailyadministration of the test molecule.

The observations are carried out by making visible the rhythms ofactivity:

control of the rhythms of activity by the light rhythm,

disappearance of rhythm control in permanent darkness,

control by the daily administration of the molecule; transitory orlasting effect.

A computer program makes it possible:

to measure the duration and the intensity of the activity, and theperiod of the rhythm in animals in free mode and during the treatment,

optionally to demonstrate, by spectral analysis, the existence ofcircadian and noncircadian (ultradien, for example) components.

Results

It clearly appears that the compounds of the invention make it possibleto have a powerful effect on the circadian rhythm via the melatoninergicsystem.

EXAMPLE E Antiarrhythmic Activity

Protocol

(Ref: Lawson J. W. et al., J. Pharmacol. Expert. Therap., 160, 22-31,1968)

The substance tested is administered intraperitoneally to a group of 3mice 30 min before exposure to anesthesia by chloroform. The animals arethen observed for 15 min. The absence of any recording of arrhythmiasand of heart rates above 200 beats/min (control: 400-480 beats/min) intwo animals at least indicates significant protection.

EXAMPLE F Platelet Aggregation-Inhibitory Activity Protocol

(Ref.: Bertele V. et al., Science, 220, 517-519, 1983

ibid, Eur. J. Pharmacol., 85, 331-333, 1982)

The compounds of the invention (100 μg/mi) are tested for their abilityto inhibit the irreversible platelet aggregation induced by sodiumarachidonate (50 μg(ml) in platelet-enriched rabbit plasma.

Inhibition of the maximum aggregation by more than 50% indicatessignificant activity for the compounds of the invention.

This in vitro test shows that the compounds of the invention are goodcandidates for the treatment of cardiovascular diseases, in particularthromboses.

EXAMPLE G Extension of the Bleeding Time

Protocol

(Ref.: Djana E. et al., Thrombosis Research, 15, 191-197, 1979) ButlerK. D. et al., Thromb. Haemostasis, 47, 4649, 1982)

The test compounds are administered orally (100 mg/kg) to a group of 5mice 1 h before standardized sectioning of the end of each tail (0.5mm).

The mice are immediately suspended vertically, their tails beingimmersed for a length of 2 cm in a test tube containing an isotonicsaline solution at 37° C.

The time required for the bleeding to stop for a period of 15 seconds isthen determined.

An extension in the bleeding time of more then 50% relative to a groupof control animals is regarded as significant for the compounds of theinvention.

This in viva test confirms the benefit of the compounds of the inventionin the treatment of cardiovascular pathologies since the compounds ofthe invention extend the bleeding time.

EXAMPLE H Hypobaric Hypoxia Test

Protocol

(Ref.: Gotti B. and Depoortere H., Circ. Cerebrale, Congres deCirculation Cerebrale (Cerebral Circulation Congress], Toulouse,105-107, 1979)

The test compounds are administered intraperitoneally (100 mg/kg) to agroup of 3 mice 30 minutes before being placed in a chamber at ahypobaric pressure of 20 cm Hg.

The extension in the survival time, with respect to a group of animalstreated with the vehicle, of more than 100% and in the absence of adepressant effect on the central nervous system indicates a cerebralprotective activity of the compounds of the invention.

EXAMPLE I Effects in the free exploratory test in C3H/He mice

Apparatus and procedure:

Behavior was assessed in a box subdivided into six equal squareexploratory units, which were interconnected by small doors. It could bedivided in half lengthwise by closing partitions. Twenty-four hoursbefore the test, each animal was randomly placed in one half of theapparatus, with the temporary partitions in place, in order to becomefamiliarized with it.

On the day of the test, the temporary partitions were removed and theanimals were observed for 10 minutes:

numbers of attempts towards the unfamiliar compartment

latency of the first entry into the unfamiliar compartment

time spent in the unfamiliar compartment

locomotion in the unfamiliar compartment

number of rears in the unfamiliar compartment

locomotion in the familiar compartment

number of rears in the familiar compartment

Experimental conditions:

Compounds were orally administered at doses of 1.5, and 25 mg/kg (in 1%HEC), 40 minutes before the test.

The central group received the vehicle under the same conditions.

Results:

Compounds were found to have desinhibitory effects in C3H/He mice, sincethey dose-dependently reduced the neophobia induced by an unfamiliarenvironment.

For example, the compound of Example 131 dose-dependently reduced theattempts and the latency, and increased the locomotion in the unfamiliarcompartment. The differences with the control group were statisticallysignificant for the 3 tested doses.

At 5 and 25 mg/kg, the compound of Example 131 significantly increasedthe time spent in the unfamiliar compartment.

At the highest dose, i.e., 25 mg/kg, the compound of Example 131significantly increased the number of rears in the unfamiliarcompartment.

Example II: Carbamides or Ureas

Substitution of the compounds of Examples 120 or 159-163 in theforegoing pharmacological Examples, especially in place of the compoundsof Examples 119 and 131, gives approximately equallystatistically-significant results.

EXAMPLE J Pharmaceutical Composition: Tablets

1000 tablets, containing a dose of 5 mg of5-(2-acetamidoethyl)-2H-1-naphtho[2,1-b]pyran

5-(2-Acetamidoethyl)-2H-1-naphtho[2, 1-b]pyran . . . 5 g

Wheat starch . . . 20 g

Maize starch . . . 20 g

Lactose . . . 30 g

Magnesium stearate . . . 2 g

Silica . . . 1 g

Hydroxypropylcellulose . . . 2 g

EXAMPLE K Pharmaceutical Composition: Tablets

1000 tablets, containing a dose of 5 mg ofN-[2-(8,9-Dihydro-7H-furo[3,2-f]chromen-1-yl) ethyl]acetamide

N-[2-(8,9-Dihydro-7H-furo[3,2-f]chromen-1-yl)ethyl]acetamide . . . 5

Wheat starch . . . 20 g

Maize starch . . . 20 g

Lactose . . . 30 g

Magnesium stearate . . . 2 g

Silica . . . 1 g

Hydroxypropylcellulose . . . 2 g

EXAMPLE KK Carbamides or Ureas

Substitution of the compounds of Examples 120 or 159-163 as the activeingredient in the compositions of Example J and Example K, in the sameamounts, provides equally satisfactory pharmaceutical compositions ofthese carbamide or urea compounds.

It is to be understood that the present invention is not to be limitedto the exact details of operation, or to the exact compounds,compositions, methods, procedures, or embodiments shown and described,as various modifications and equivalents will be apparent to one skilledin the art, wherefore the present invention is to be limited only by thefull scope which can be legally accorded to the appended claims.

We claim:
 1. A compound selected from those of formula (I): ##STR39## inwhich: R¹ represents a (C₁ -C₄) alkylene chain which is unsubstituted orsubstituted by a radical chosen from alkyl, hydroxyl, alkoxycarbonyl,and carboxyl;R² represents hydrogen or alkyl; R³ represents a group offormula R³² : ##STR40## in which X represents oxygen or sulfur, mrepresents zero or 1 to 3, inclusive, and R⁶ represents a radical chosenfrom hydrogen, unsubstituted or substituted alkyl, unsubstituted orsubstituted alkenyl, unsubstituted or substituted alkynyl, unsubstitutedor substituted cycloalkyl, and unsubstituted or substituteddicycloalkylalkyl; A represents a chain of formula --O--A¹ in which A¹is a chain chosen from (C₂ -C₅)alkylene, (C₂ -C₅)alkenylene, and (C₂-C₅)alkynylene; A¹ being unsubstituted or substituted by one or a numberof groups chosen from alkyl, alkoxy, hydroxyl, and oxo; Y forming, withthe benzene ring to which it is bonded, a Y¹ group selected from thegroup consisting of naphthalene, partially hydrogenated naphthalene,benzofuran, partially hydrogenated benzofuran, benzothiophene, partiallyhydrogenated benzothiophene, and indole; it being understood that: theexpression "substituted" relating to the terms "alkyl", "alkenyl", and"alkynyl" means that these groups are substituted by one or a number ofradicals chosen from halogen, alkyl, and alkoxy, the expression"substituted" relating to the term "cycloalkyl" or "dicycloalkylalkyl"means that these groups are substituted by one or a number of radicalschosen from: alkyl, alkoxy, hydroxyl, and the oxo group, the terms"alkyl" and "alkoxy" denote radicals containing 1 to 6 carbon atoms,inclusive, the terms "alkeniyl" and "alkynyl" denote unsaturatedradicals having 2 to 6 carbon atoms, inclusive, the term "cycloalkyl"denotes a saturated or unsaturated cycloalkyl group having 3 to 8 carbonatoms, inclusive, its enantiomers and diastereoisomers, and an additionsalt thereof with a pharmaceutically-acceptable base.
 2. A compound ofclaim 1, which isN-[2-(2,3-dihydro-2-methyl-1-naphtho[2,1-b]furan-4-yl)ethyl]-N'-methylurea.3. A compound of claim 1, which isN-[2-(8,9-Dihydro-7H-furo[3,2-f]chromen-1-yl)ethyl]-N'-propylurea.
 4. Acompound of claim 1, which isN-Butyl-N'-[2-(8,9-dihydro-7H-furo[3,2-f]chromen-1-yl)ethyl]urea.
 5. Acompound of claim 1, which isN-Cyclopropyl-N'-[2-(8,9-dihydro-7H-furo[3,2-f]chromen-1-yl)ethyl]thiourea.6. A compound of claim 1, which isN-[2-(8,9-Dihydro-7H-furo[3,2-f]chromen-1-yl)ethyl]-N'-propylthiourea.7. A compound of claim 1, which isN-Butyl-N'-[2-(8,9-dihydro-7H-furo[3,2-f]chromen-1-yl)ethyl]thiourea. 8.A compound of claim 1, which isN-[2-(8,9-Dihydro-7H-furo[3,2-f]chromen-1-yl)ethyl]-N'-methylurea.
 9. Acompound of claim 1, which isN-[2-(8,9-Dihydro-7H-furo[3,2-f]chromen-1-yl)ethyl]-N'-isopropylurea.10. A compound of claim 1, which isN-Cyclobutyl-N'-[2-(8,9-dihydro-7H-furo[3,2-f]chromen-1-yl)ethyl]urea.11. A compound as claimed in claim 1, wherein Y¹ is a benzofuran group.12. A compound as claimed in claim 1, wherein Y¹ is apartially-hydrogenated benzofuran group.
 13. A pharmaceuticalcomposition containing a compound of claim 1 in combination with one ora number of pharmaceutically-acceptable excipients.
 14. A method oftreating a mammal afflicted with a disorder of the melatoninergic systemcomprising the step of administering to the said mammal an amount of acompound as claimed in claim 1 which is effective to alleviate the saiddisorder.